Next Article in Journal / Special Issue
Therapeutic Approaches Using Host Defence Peptides to Tackle Herpes Virus Infections
Previous Article in Journal
Protection against Mucosal SHIV Challenge by Peptide and Helper-Dependent Adenovirus Vaccines
Previous Article in Special Issue
The Human Cytomegalovirus Major Immediate-Early Proteins as Antagonists of Intrinsic and Innate Antiviral Host Responses

Viruses 2009, 1(3), 965-978; doi:10.3390/v1030965

Review
Cellular Players in the Herpes Simplex Virus Dependent Apoptosis Balancing Act
Marie L. Nguyen 1,* and John A. Blaho 2
1
Department of Microbiology and Immunology, Des Moines University, Des Moines, IA, USA
2
Department of Microbiology, Mount Sinai School of Medicine, New York, NY, USA; E-Mail: john.blaho@mssm.edu
Author to whom correspondence should be addressed; E-Mail: marie.nguyen@dmu.edu; Tel.: +1-515-271-1400; Fax: +1-515-271-1543.
Received: 30 September 2009; in revised form: 16 November 2009 / Accepted: 17 November 2009 /
Published: 18 November 2009

Abstract

: Apoptosis is triggered as an intrinsic defense against numerous viral infections. Almost every virus encodes apoptotic modulators, and the herpes simplex viruses (HSV) are no exception. During HSV infection, there is an intricate balance between pro- and anti-apoptotic factors that delays apoptotic death until the virus has replicated. Perturbations in the apoptotic balance can cause premature cell death and have the potential to dramatically alter the outcome of infection. Recently, certain cellular genes have been shown to regulate sensitivity to HSV-dependent apoptosis. This review summarizes current knowledge of the cellular genes that impact the apoptotic balance during HSV infection.
Keywords:
Herpes Simplex Virus; apoptosis; virus-host interactions

1. Introduction

Apoptosis is a form of programmed cell death that is triggered during normal development and as a response to cellular stresses. Apoptotic cells display unique biochemical and morphological changes that distinguish them from cells dying through other pathways. Apoptotic morphological characteristics include membrane blebbing, chromatin condensation, nuclear fragmentation, and exposure of phosphatidylserine moieties [1-3]. There are two well defined pathways for the induction of apoptosis [4,5]. In one pathway, the extrinsic pathway, the signal is initiated at the cell surface [6]. Here, death factors bind to receptors embedded in the plasma membrane. The ligand:receptor binding triggers the assembly of large multiprotein complexes called death inducing signaling complexes (DISCs). A key biochemical characteristic of classical apoptosis is the activation of a specific set of cysteinyl aspartate proteases, called caspases. DISC formation includes the recruitment of the initiator caspase 8 to the complex that causes its autoactivation. Active caspase 8 cleaves and activates downstream effector caspases, such as caspases 3 and 7. Effector caspases cleave cellular proteins which maintain the integrity of the cell, which leads to the biochemical and morphological changes associated with apoptosis.

The other major signaling pathway leading to apoptosis is the intrinsic pathway [7]. Intrinsic triggers of apoptosis include DNA damage, heat-shock, and damage due to reactive oxygen species. This response causes changes in the ratio of pro- and antiapoptotic Bcl-2 family members within the mitochondrial membrane, which leads to a release of cytochrome c into the cytoplasm [8,9]. Cytochrome c forms complexes with apaf-1 and procaspase 9 to form a large multicomponent structure known as the apoptosome, causing the activation of caspase 9 [5,8]. Active caspase 9 goes on to activate effector caspases and the apoptosis inducing signaling pathways converge at this point. An additional layer of complexity is added to these apoptotic signaling pathways as crosstalk between the two pathways exists. For example, caspase 8 activated during the extrinsic pathway cleaves the Bid Bcl-2 family member [5]. The cleaved product, tBid, acts as a positive regulator of mitochondrial cytochrome c release. This release, in turn, initiates the intrinsic apoptotic pathway and amplifies the extrinsic apoptotic death signal.

The apoptotic pathway is often triggered as a consequence of viral infection. Therefore, almost all viruses encode genes to modulate the apoptotic pathway. It is important to note that although DNA viruses seem to universally express anti-apoptotic proteins, RNA viruses rarely do [10]. One potential explanation for this observation is that the ability of RNA viruses to replicate rapidly may allow them to avoid the problems associated with apoptosis. [11]. DNA viruses use a diverse array of mechanisms to impair the apoptotic response of cells. Small DNA tumor viruses, like human papillomavirus and adenovirus block the effects of p53 that normally functions to upregulate multiple pro-apoptotic cellular genes during times of cell stress [12-14]. Insect viruses, such as Baculovirus, produce proteins which inhibit caspases [15]. A subset of herpesviruses, including Kaposi’s sarcoma herpes virus / human herpes virus 8 and Epstein Barr virus encode genes that are homologous to cellular anti-apoptotic Bcl-2 family members [16-18]. Herpes simplex viruses (HSVs) encode a number of genes that modulate cellular apoptotic pathways.

HSV infection triggers the apoptotic pathway early in infection [19-22]. However, as the viral infection progresses, anti-apoptotic proteins produced by the early and late herpes viral genes block apoptosis from ensuing [19,23,24]. This sets up an intricate balance between the pro- and anti-apoptotic factors in the cell. When the anti-apoptotic factors are not efficiently produced, the balance is upset and the HSV-infected cells die through an apoptotic pathway, Herpes Simplex Virus-Dependent Apoptosis (HDAP) [19,25,26]. Initial research on HDAP focused on the viral factors modulating apoptosis during infection. These studies identified a number of viral proteins which act to block apoptosis during infection. They include immediate early genes, such as ICP27 and ICP4, that likely act as upstream regulators of later anti-apoptotic viral genes [19,25,26]. Deletion of either of these genes from the viral genome results in a replication defective and pro-apoptotic virus. The early gene, ICP10 PK, plays an anti-apoptotic role during HSV-2 infection [27,28]. Late viral genes shown to possess anti-apoptotic properties include Us3, gD, gJ, and the latency associated transcripts [29-33]. Single deletions of these late genes generate viruses that fail to cause apoptosis to the same extent as ICP27 and ICP4-null viruses, suggesting that the late viral genes act in concert to prevent apoptosis during a wild type HSV infection.

HSV is best known as the causative agent of cold sores and genital herpes. However, when the virus reaches tissues other than the mucosal epithelium, it causes much more serious disease such as potentially blinding cases of keratitis and life threatening encephalitis. Animal and human studies have provided support for a role for apoptosis in the pathogenesis severe HSV disease. Specifically, apoptotic cells have been detected in animal models of herpes simplex keratitis [34-36]. The amount of apoptosis inversely correlates with the severity of disease [37,38]. This result suggests that apoptosis is acting as an antiviral defense mechanism of infected cells. Apoptosis has also been found to be a feature of herpes simplex encephalitis (HSE) [28,39,40]. In this case, however, there seems to be a positive correlation between the severity of disease and extent of apoptosis [40,41]. Thus, triggering apoptosis may contribute to the virulence of HSV during encephalitis. Together, the evidence suggests that cell-type determinants mediate the way in which apoptosis impacts HSV pathogenesis.

2. Results and Discussion

The majority of the early studies on HDAP utilized immortalized cell lines typically used to propagate HSV, i.e., Vero and HEp-2/HeLa cells, which provided insight into the viral factors involved in this response. Yet, later studies demonstrated the existence of cell-type differences in the response to HDAP, indicating that cellular factors play an important role in this process. For example, primary epithelial cells from mammary tissues and primary skin fibroblasts display resistance to HDAP [42,43]. Primary murine neuronal cells also seem to show a similar apoptotic regulation during wild type HSV-1 infection [44-46]. Recently, a number of specific cellular factors modulating HDAP have been identified. These cellular genes can be classified as caspases, Bcl-2 family members, NF-κB, and oncogenic genes.

2.1 Caspases

Multiple studies demonstrate that HDAP is caspase-dependent [19,23,47-50]. The small peptide pan-caspase inhibitors, e.g., z-VAD-fmk, are efficient suppressors of the biochemical and morphological apoptotic phenotypes found during HDAP. The use of specific caspase inhibitors has allowed elucidation of the pathway by which apoptosis is triggered during infection [47]. An inhibitor of caspase 9, z-LEHD-fmk, suppressed HDAP in HEp-2 cells to an extent similar to that of the pan-caspase inhibitor. However, a caspase 8 inhibitor, z-LETD-fmk failed to suppress HDAP, even though it was capable of suppressing apoptosis induced by tumor necrosis factor and cycloheximide. Furthermore, cytochrome c was released in a caspase-independent manner during HDAP [47]. These results led to the conclusion that HDAP occurs through the intrinsic pathway of apoptosis.

One effector caspase commonly utilized in the intrinsic pathway is caspase 3. Studies in our laboratory using genetic analysis demonstrated that caspase 3 is necessary for HDAP. This work stemmed from our observation that the tumor cells that were resistant to HDAP were also highly resistant to other forms of apoptotic induction. We hypothesized that the HDAP resistance was due to the acquisition of mutations in cellular apoptotic pathways, which blocked apoptosis in general [43]. One such tumor cell line was the breast cancer MCF-7 cells. MCF-7 cells are known to be defective for a key component of the apoptotic cascade, caspase 3 [51]. When MCF-7 cells in which caspase 3 expression was restored (MCF-7 C3) and caspase 3-null counterparts (MCF-7 PV) were infected with a pro-apoptotic HSV mutant, the MCF-7 C3 cells displayed membrane blebbing and biochemical features of apoptosis, while similarly infected MCF-7 PV cells did not [49]. This finding not only demonstrated that restoring the apoptotic pathway sensitized these cells to HDAP, but also identified caspase 3 as a cellular determinant for HDAP. Interestingly, caspase 3 has also been found to play a role in the apoptosis during influenza virus infection [52]. Inhibition of caspase 3 leads to a reduction in the influenza virus titer. A subset of caspase 3 is found in the active form during a wild type HSV infection [49]. Whether caspase 3 similarly contributes to HSV replication efficiency has yet to be determined.

It is of note that the ICP22 protein of HSV has been shown to be cleaved by caspases during infection with a mutant, pro-apoptotic virus [53]. The biological significance of this cleavage has yet to be elucidated, as the cleaved form of the protein does not accumulate during a wild type HSV-1 infection, and the function of the cleaved form has not been defined.

2.2. Bcl-2 Family Members

The Bcl-2 family comprises of pro-and anti-apoptotic proteins all sharing conserved protein motifs, known as Bcl-2 homology (BH) domains [54]. Most of these members reside within the mitochondrial membrane. The ratio and activities of the pro- and anti apoptotic Bcl-2 family members in this region determines the release of cytochrome c from the mitochondria and subsequent initiation of the intrinsic apoptotic pathway. HSV has been shown to block the activities of certain pro-apoptotic Bcl-2 family members. HSV Us3 blocked cell death and caspase activation induced by overexpression of Bax, Bad, or Bid [55,56]. In fact, Bax appears to accumulate at mitochondria during HDAP [47]. Cartier et al. determined that Bad is phosphorylated in a Us3 dependent manner during HSV infection [57]. This may contribute to its ability to block Bad activity. In other studies, exogenous expression of the anti-apoptotic Bcl-2 protein blocked apoptosis induced by HSV infection of HEp-2 and the U-937 lymphoma cell line [48,58]. In U-937 cells this Bcl-2 overexpression led to increased HSV-2 yields, suggesting that manipulation of apoptotic pathways can influence the efficiency of virus replication, at least in certain cell types [58].

2.3. NF-ĸB

NF-ĸB is a transcription factor that plays a major role in inflammation and the immune response [59]. Inactive NF-ĸB is bound to an inhibitory protein, IĸB, and sequestered in the cytoplasm. Following exposure to a proper stimulus, IĸB is phosphorylated and degraded, and NF-ĸB translocates to the nucleus [60,61]. There, it induces the expression of a number of genes involved in cell survival, proliferation, and inflammation [62,63]. Early studies demonstrated that NF-ĸB translocates to the nucleus during HSV-1 infection and the timing of this translocation coincides with apoptosis prevention [64-67]. A pro-apoptotic mutant virus of HSV-1 did not cause a similar translocation [65]. Furthermore, cells which expressed a dominant negative form of IĸBα, IĸBαDN, display apoptosis when infected with wild type HSV [65-67]. These results support a role for NF-ĸB in the prevention of apoptosis during HSV-1 infection. However, others have reported that NF-ĸB may provide important functions other than apoptosis prevention during HSV-1 infection [68,69]. For example, studies suggested that NFĸ-B activation is linked to the activation of a key regulator of the innate immune response, PKR [68,69].

More recently, studies from our group have provided additional information regarding a role for NF-ĸB in apoptosis prevention. HEp-2 cells infected with HSV-2 were found to display NF-ĸB nuclear translocation during the time of apoptosis prevention [70]. This result suggested that NF-ĸB’s role in the prevention of apoptosis during infection with HSV-2 is similar to that of its role in HSV-1 infection. Additionally, HSV infection led to NF-ĸB translocation in corneal epithelial cells, implicating NF-ĸB in apoptosis prevention in herpes simplex keratitis [71]. However, not all of HSV’s capacity to block apoptosis can be attributed to NF-ĸB. Results from our group have demonstrated that HSV-1 is effective at blocking apoptosis in HEp-2 cells induced by Fas ligand and cycloheximide [72]. Although this prevention corresponded with NF-ĸB nuclear translocation, HSV-1 was still capable of blocking Fas-mediated apoptosis in HEp-2 cells constitutively expressing IĸBαDN [72]. This result led to the conclusion that HSV-1 possesses NF-ĸB-independent mechanisms of blocking apoptosis.

2.4. Oncogenic Genes

Oncogenes were first implicated as mediators of HDAP in studies comparing the sensitivities of human cancer cells with that of primary cells [42]. The studies indicated that the transformation status of cells correlates with their sensitivity to the viral induced apoptosis. Subsequently, differences between the immortalized, but not transformed Vero cell line and that of the highly sensitive transformed HEp-2 cells revealed the existence of a cellular protein that facilitates apoptosis during infection [73]. The Vero cells require production of the facilitator protein, while HEp-2 cells are independent of it. All primary cells tested to date have been resistant to HDAP based upon caspase substrate cleavage, chromatin condensation, membrane blebbing, and DNA laddering analyses [43]. Remarkably, even cells of the same patient derived from a mammary tumor and the surrounding normal tissue displayed opposite sensitivity to HDAP [43]. These data led to the hypothesis that genetic changes occurring during tumor development sensitized cells to HDAP.

Our group tested the aforementioned hypothesis using a tumor model system in which the cellular transformation status could be experimentally manipulated. This model makes use of the fact that the human cervical cancer derived HeLa cell line requires continuous expression of human papillomavirus (HPV) genes in order to maintain a tumorigenic phenotype [74-76]. Suppressing the HPV 18 E6 and E7 via the expression of the papillomavirus E2 transcriptional repressor leads to reductions in cell growth, and eventually senescence of the cells [74,77-79]. We found that repression of HPV E6 and E7 reduced the sensitivity of HeLa cells to HDAP [80]. Furthermore, adding back expression of HPV E6, but not E7, restored HeLa cell HDAP sensitivity. These studies allowed us to narrow our search for oncogenic HDAP mediators to those altered by HPV E6. HPV E6 is a multifunctional protein, known to affect the function of at least a dozen cellular proteins [81]. So far, two of these proteins, p53 and telomerase, have been identified as regulators of HDAP sensitivity.

2.4.1. p53

HPV E6’s most well studied function is the inactivation of the cellular tumor suppressor, p53. The p53 protein has been dubbed the “guardian of the genome” due to its role in preventing genetic mutations in the cell lineage [82]. The levels of p53 protein are usually kept low in healthy cells due to an extremely rapid turnover mediated by mdm2. However in response to cell stresses, p53 is stabilized, accumulates within the cell, and forms tetramers. The tetramers of p53 act as a transcriptional factor to induce a variety of genes that are involved in DNA repair, cell cycle arrest, and apoptosis. HPV E6 forms complexes with p53 and the cellular ubiquitin ligase, E6AP/UBE3A, to cause p53 ubiquitination and degradation [83,84]. Inactivation of p53 can also be achieved by expressing a mutant p53 molecule, which oligomerizes with wild type p53, but lacks the ability for transcriptional activation [85,86]. In the HeLa cells, we found that constitutive expression of a dominant negative p53 mutant was capable of sensitizing the HeLa cells to HDAP to the same extent as HPV E6 [80]. This result demonstrated that p53 inactivation can sensitize cells to HDAP.

Interestingly, several reports provide evidence for direct effects of HSV on p53 levels. Like HPV E6, the ICP0 protein of HSV-1 was found to bind to and mediate the ubiquitination of p53 in vitro [87]. A similar ICP0-dependent ubiquitination was apparent in murine fibroblasts cotransfected with human p53 and ICP0 expression plasmids. However, the destabilization of p53 is not detected during an HSV infection. In fact, p53 was found to be phosphorylated and stabilized in human foreskin fibroblasts and primary mammary epithelial cells infected with HSV-1 [88] and [Nguyen and Blaho, unpublished results]. Furthermore, human embryonic lung cells infected with a replication defective mutant of HSV, which expresses ICP0, displayed p53 stabilization and p21 upregulation [89]. Therefore, the effects of ICP0 on p53 may be overridden by other HSV genes during a complete virus infection.

2.4.2. Telomerase

The hTERT gene encodes the catalytic component of human telomerase [90-93]. Telomerase is the enzyme which replicates the ends of chromosomes (telomeres) [94]. Telomeres are typically shorter in adult somatic cells than those of embryonic and tumor origin [95-97]. Without telomerase, telomeres progressively shorten and when they reach a critical length, cells stop dividing or die through a process known as crisis [98]. Because HPV E6 is known to increase telomerase activity through upregulation of hTERT [99], we studied the effects of hTERT expression on sensitivity to HDAP. HeLa cells constitutively overexpressing hTERT, were as sensitive to HDAP as those cells expressing only HPV E6 [80]. Furthermore, primary mammary epithelial cells immortalized by hTERT expression are sensitive to HDAP, while primary mammary epithelial cells are resistant [Nguyen and Blaho, unpublished results]. Therefore, hTERT overexpression sensitizes cells to viral apoptosis. Contrary to HDAP, hTERT expression has been reported to decrease sensitivity to various other apoptotic stimuli, including oxidative stress, serum deprivation, dsDNA breaks, and cisplatinum [100-103]. Thus, HSV seems to be manipulating the apoptotic pathway in a unique way.

3. Conclusions

Apoptosis is a common cellular defense against pathogens. As a consequence, many successful pathogens possess an ability to modulate the apoptotic response. Over a decade of research has revealed much about the regulation of apoptosis during HSV infection. We know that apoptosis is initially triggered during the expression of viral immediate early genes, but this cell death signal is later squelched by the production of antiapoptotic viral factors. In this way, an HSV-infected cell walks a fine line of apoptotic balance during a productive infection, delaying cell death, presumably until the moment optimal for virus replication.

Viruses 01 00965 g001 1024
Figure 1. Viral and Cellular players in the HSV dependent apoptosis balancing act. Shown here is a current model of apoptotic modulation during an HSV infection. During the early stages of viral infection, immediate early viral gene expression triggers apoptosis. The cellular factors, hTERT and caspase 3, contribute to apoptosis induction. However, at later times post infection, early and late viral anti-apoptotic genes are produced, which block apoptosis from proceeding. Bcl-2, NF-ĸB, and p53 are cellular genes that contribute to the blocking of apoptosis during infection. Collectively, this sets up a delicate balance between the pro- and anti-apoptotic factors during a productive HSV infection.

Click here to enlarge figure

Figure 1. Viral and Cellular players in the HSV dependent apoptosis balancing act. Shown here is a current model of apoptotic modulation during an HSV infection. During the early stages of viral infection, immediate early viral gene expression triggers apoptosis. The cellular factors, hTERT and caspase 3, contribute to apoptosis induction. However, at later times post infection, early and late viral anti-apoptotic genes are produced, which block apoptosis from proceeding. Bcl-2, NF-ĸB, and p53 are cellular genes that contribute to the blocking of apoptosis during infection. Collectively, this sets up a delicate balance between the pro- and anti-apoptotic factors during a productive HSV infection.
Viruses 01 00965 g001 1024

Soon after the viral factors involved in apoptosis were elucidated, cell specific differences in sensitivity to HSV induced apoptosis were recognized. The identification of cellular proteins which mediated these cell type specificities followed (Figure 1). The cellular mediators of apoptosis Bcl-2 family members and caspases relay the signal from the initiation to execution of cell death during HSV infection. Exploiting the apoptotic proteins that are necessary for HDAP may clarify HDAP’s impact on viral pathogenesis. Less predictably, perhaps, were the findings that at least two genes involved in tumorigenesis, p53 and hTERT, influence the ability of the infected cell to respond to viral apoptotic triggers. At this time, the molecular mechanisms whereby these genes confer their effects is still unclear. What is clear is that the regulation of apoptosis within an HSV infected cell is much more complex that originally anticipated. We have yet to learn how many more cellular players may impact the HSV dependent apoptosis balancing act.

We would like to thank Rachel Kraft, Kristen Peña, and Elisabeth Gennis for their work that contributed to the studies described in this review. The studies which serve as the basis of this review were supported by grants from the U.S.P.H.S. (AI038873 and AI48582 to J.A.B. and AI07647 and CA088796 for M.L.N.) M.L.N. would also like to thank the Iowa Osteopathic Education and Research Fund for support.

References

  1. Fadok, V.A.; Bratton, D.L.; Frasch, S.C.; Warner, M.L.; Henson, P.M. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ 1998, 5, 551–562. [Google Scholar]
  2. Kerr, J.F.; Wyllie, A.H.; Currie, A.R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972, 26, 239–257. [Google Scholar]
  3. Wyllie, A.H.; Kerr, J.F.; Currie, A.R. Cell death: the significance of apoptosis. Int Rev Cytol 1980, 68, 251–306. [Google Scholar] [CrossRef]
  4. Nagata, S. Apoptosis by death factor. Cell 1997, 88, 355–365. [Google Scholar] [CrossRef]
  5. Sun, X.M.; MacFarlane, M.; Zhuang, J.; Wolf, B.B.; Green, D.R.; Cohen, G.M. Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. J Biol Chem 1999, 274, 5053–5060. [Google Scholar] [CrossRef]
  6. Ashkenazi, A.; Dixit, V.M. Death receptors: signaling and modulation. Science 1998, 281, 1305–1308. [Google Scholar] [CrossRef]
  7. Green, D.R.; Evan, G.I. A matter of life and death. Cancer cell 2002, 1, 19–30. [Google Scholar] [CrossRef]
  8. Green, D.; Kroemer, G. The central executioners of apoptosis: caspases or mitochondria? Trends Cell Biol 1998, 8, 267–271. [Google Scholar] [CrossRef]
  9. Petit, P.X.; Susin, S.A.; Zamzami, N.; Mignotte, B.; Kroemer, G. Mitochondria and programmed cell death: back to the future. FEBS letters 1996, 396, 7–13. [Google Scholar] [CrossRef]
  10. Koyama, A.H.; Adachi, A.; Irie, H. Physiological significance of apoptosis during animal virus infection. Int Rev Immunol 2003, 22, 341–359. [Google Scholar] [CrossRef]
  11. Blaho, J.A. Virus infection and apoptosis (issue II) an introduction: cheating death or death as a fact of life? Int Rev Immunol 2004, 23, 1–6. [Google Scholar] [CrossRef]
  12. Querido, E.; Marcellus, R.C.; Lai, A.; Charbonneau, R.; Teodoro, J.G.; Ketner, G.; Branton, P.E. Regulation of p53 levels by the E1B 55-kilodalton protein and E4orf6 in adenovirus-infected cells. J Virol 1997, 71, 3788–3798. [Google Scholar]
  13. Scheffner, M.; Munger, K.; Byrne, J.C.; Howley, P.M. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci U S A 1991, 88, 5523–5527. [Google Scholar] [CrossRef]
  14. Werness, B.A.; Levine, A.J.; Howley, P.M. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 1990, 248, 76–79. [Google Scholar]
  15. Clem, R.J.; Fechheimer, M.; Miller, L.K. Prevention of apoptosis by a baculovirus gene during infection of insect cells. Science 1991, 254, 1388–1390. [Google Scholar]
  16. Cheng, E.H.; Nicholas, J.; Bellows, D.S.; Hayward, G.S.; Guo, H.G.; Reitz, M.S.; Hardwick, J.M. A Bcl-2 homolog encoded by Kaposi sarcoma-associated virus, human herpesvirus 8, inhibits apoptosis but does not heterodimerize with Bax or Bak. Proc Natl Acad Sci U S A 1997, 94, 690–694. [Google Scholar] [CrossRef]
  17. Sarid, R.; Sato, T.; Bohenzky, R.A.; Russo, J.J.; Chang, Y. Kaposi's sarcoma-associated herpesvirus encodes a functional bcl-2 homologue. Nat Med 1997, 3, 293–298. [Google Scholar] [CrossRef]
  18. Takayama, S.; Cazals-Hatem, D.L.; Kitada, S.; Tanaka, S.; Miyashita, T.; Hovey, L.R.; Huen, D.; Rickinson, A.; Veerapandian, P.; Krajewski, S. Evolutionary conservation of function among mammalian, avian, and viral homologs of the Bcl-2 oncoprotein. DNA Cell Biol 1994, 13, 679–692. [Google Scholar] [CrossRef]
  19. Aubert, M.; Blaho, J.A. The herpes simplex virus type 1 regulatory protein ICP27 is required for the prevention of apoptosis in infected human cells. J Virol 1999, 73, 2803–2813. [Google Scholar]
  20. Koyama, A.H.; Adachi, A. Induction of apoptosis by herpes simplex virus type 1. J Gen Virol 1997, 78, 2909–2912. [Google Scholar]
  21. Sanfilippo, C.M.; Blaho, J.A. ICP0 gene expression is a herpes simplex virus type 1 apoptotic trigger. J Virol 2006, 80, 6810–6821. [Google Scholar] [CrossRef]
  22. Sanfilippo, C.M.; Chirimuuta, F.N.; Blaho, J.A. Herpes Simplex Virus Type 1 Immediate-Early Gene Expression Is Required for the Induction of Apoptosis in Human Epithelial HEp-2 Cells. J Virol 2004, 78, 224–239. [Google Scholar] [CrossRef]
  23. Galvan, V.; Roizman, B. Herpes simplex virus 1 induces and blocks apoptosis at multiple steps during infection and protects cells from exogenous inducers in a cell- type-dependent manner. Proc Natl Acad Sci U S A 1998, 95, 3931–3936. [Google Scholar] [CrossRef]
  24. Koyama, A.H.; Miwa, Y. Suppression of apoptotic DNA fragmentation in herpes simplex virus type 1-infected cells. J Virol 1997, 71, 2567–2571. [Google Scholar]
  25. Aubert, M.; Blaho, J.A. Modulation of apoptosis during HSV infection in human cells. Microbes Infect 2001, 3, 859–866. [Google Scholar] [CrossRef]
  26. Leopardi, R.; Roizman, B. The herpes simplex virus major regulatory protein ICP4 blocks apoptosis induced by the virus or by hyperthermia. Proc Natl Acad Sci U S A 1996, 93, 9583–9587. [Google Scholar] [CrossRef]
  27. Han, J.Y.; Miller, S.A.; Wolfe, T.M.; Pourhassan, H.; Jerome, K.R. Cell type-specific induction and inhibition of apoptosis by Herpes Simplex virus type 2 ICP10. J Virol 2009, 83, 2765–2769. [Google Scholar] [CrossRef]
  28. Perkins, D.; Gyure, K.A.; Pereira, E.F.; Aurelian, L. Herpes simplex virus type 1-induced encephalitis has an apoptotic component associated with activation of c-Jun N-terminal kinase. J Neurovirol 2003, 9, 101–111. [Google Scholar]
  29. Jerome, K.R.; Fox, R.; Chen, Z.; Sears, A.E.; Lee, H.; Corey, L. Herpes simplex virus inhibits apoptosis through the action of two genes, Us5 and Us3. J Virol 1999, 73, 8950–8957. [Google Scholar]
  30. Leopardi, R.; Van Sant, C.; Roizman, B. The herpes simplex virus 1 protein kinase US3 is required for protection from apoptosis induced by the virus. Proc Natl Acad Sci U S A 1997, 94, 7891–7896. [Google Scholar] [CrossRef]
  31. Perng, G.C.; Jones, C.; Ciacci-Zanella, J.; Stone, M.; Henderson, G.; Yukht, A.; Slanina, S.M.; Hofman, F.M.; Ghiasi, H.; Nesburn, A.B.; Wechsler, S.L. Virus-induced neuronal apoptosis blocked by the herpes simplex virus latency-associated transcript. Science 2000, 287, 1500–1503. [Google Scholar] [CrossRef]
  32. Zhou, G.; Galvan, V.; Campadelli-Fiume, G.; Roizman, B. Glycoprotein D or J Delivered in trans Blocks Apoptosis in SK-N-SH Cells Induced by a Herpes Simplex Virus 1 Mutant Lacking Intact Genes Expressing Both Glycoproteins. J Virol 2000, 74, 11782–11791. [Google Scholar] [CrossRef]
  33. Zhou, G.; Roizman, B. The domains of glycoprotein D required to block apoptosis depend on whether glycoprotein D is present in the virions carrying herpes simplex virus 1 genome lacking the gene encoding the glycoprotein. J Virol 2001, 75, 6166–6172. [Google Scholar] [CrossRef]
  34. Miles, D.; Athmanathan, S.; Thakur, A.; Willcox, M. A novel apoptotic interaction between HSV-1 and human corneal epithelial cells. Curr Eye Res 2003, 26, 165–174. [Google Scholar] [CrossRef]
  35. Qian, H.; Atherton, S. Apoptosis and increased expression of Fas ligand after uniocular anterior chamber (AC) inoculation of HSV-1. Curr Eye Res 2003, 26, 195–203. [Google Scholar] [CrossRef]
  36. Wilson, S.E.; Pedroza, L.; Beuerman, R.; Hill, J.M. Herpes simplex virus type-1 infection of corneal epithelial cells induces apoptosis of the underlying keratocytes. Exp Eye Res 1997, 64, 775–779. [Google Scholar] [CrossRef]
  37. Miles, D.H.; Willcox, M.D.; Athmanathan, S. Ocular and neuronal cell apoptosis during HSV-1 infection: a review. Curr Eye Res 2004, 29, 79–90. [Google Scholar] [CrossRef]
  38. Zheng, X.; Silverman, R.H.; Zhou, A.; Goto, T.; Kwon, B.S.; Kaufman, H.E.; Hill, J.M. Increased severity of HSV-1 keratitis and mortality in mice lacking the 2-5A-dependent RNase L gene. Invest Ophthalmol Vis Sci 2001, 42, 120–126. [Google Scholar]
  39. DeBiasi, R.L.; Kleinschmidt-DeMasters, B.K.; Weinberg, A.; Tyler, K.L. Use of PCR for the diagnosis of herpesvirus infections of the central nervous system. J Clin Virol 2002, 25, S5–11. [Google Scholar] [CrossRef]
  40. Sabri, F.; Granath, F.; Hjalmarsson, A.; Aurelius, E.; Skoldenberg, B. Modulation of sFas indicates apoptosis in human herpes simplex encephalitis. J Neuroimmunol 2006, 171, 171–176. [Google Scholar] [CrossRef]
  41. Geiger, K.D.; Nash, T.C.; Sawyer, S.; Krahl, T.; Patstone, G.; Reed, J.C.; Krajewski, S.; Dalton, D.; Buchmeier, M.J.; Sarvetnick, N. Interferon-gamma protects against herpes simplex virus type 1-mediated neuronal death. Virology 1997, 238, 189–197. [Google Scholar] [CrossRef]
  42. Aubert, M.; Blaho, J.A. Viral oncoapoptosis of human tumor cells. Gene Ther 2003, 10, 1437–1445. [Google Scholar] [CrossRef]
  43. Nguyen, M.L.; Kraft, R.M.; Blaho, J.A. Susceptibility of cancer cells to herpes simplex virus-dependent apoptosis. J Gen Virol 2007, 88, 1866–1875. [Google Scholar] [CrossRef]
  44. Ahmed, M.; Lock, M.; Miller, C.G.; Fraser, N.W. Regions of the herpes simplex virus type 1 latency-associated transcript that protect cells from apoptosis in vitro and protect neuronal cells in vivo. J Virol 2002, 76, 717–729. [Google Scholar] [CrossRef]
  45. Asano, S.; Honda, T.; Goshima, F.; Nishiyama, Y.; Sugiura, Y. US3 protein kinase of herpes simplex virus protects primary afferent neurons from virus-induced apoptosis in ICR mice. Neurosci Lett 2000, 294, 105–108. [Google Scholar] [CrossRef]
  46. Branco, F.J.; Fraser, N.W. Herpes simplex virus type 1 latency-associated transcript expression protects trigeminal ganglion neurons from apoptosis. J Virol 2005, 79, 9019–9025. [Google Scholar] [CrossRef]
  47. Aubert, M.; Pomeranz, L.E.; Blaho, J.A. Herpes simplex virus blocks apoptosis by precluding mitochondrial cytochrome c release independent of caspase activation in infected human epithelial cells. Apoptosis 2007, 12, 19–35. [Google Scholar] [CrossRef]
  48. Galvan, V.; Brandimarti, R.; Munger, J.; Roizman, B. Bcl-2 blocks a caspase-dependent pathway of apoptosis activated by herpes simplex virus 1 infection in HEp-2 cells. J Virol 2000, 74, 1931–1938. [Google Scholar] [CrossRef]
  49. Kraft, R.M.; Nguyen, M.L.; Yang, X.H.; Thor, A.D.; Blaho, J.A. Caspase 3 activation during herpes simplex virus 1 infection. Virus Res 2006, 120, 163–175. [Google Scholar] [CrossRef]
  50. Zachos, G.; Koffa, M.; Preston, C.M.; Clements, J.B.; Conner, J. Herpes simplex virus type 1 blocks the apoptotic host cell defense mechanisms that target Bcl-2 and manipulates activation of p38 mitogen-activated protein kinase to improve viral replication. J Virol 2001, 75, 2710–2728. [Google Scholar] [CrossRef]
  51. Janicke, R.U.; Sprengart, M.L.; Wati, M.R.; Porter, A.G. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 1998, 273, 9357–9360. [Google Scholar] [CrossRef]
  52. Wurzer, W.J.; Planz, O.; Ehrhardt, C.; Giner, M.; Silberzahn, T.; Pleschka, S.; Ludwig, S. Caspase 3 activation is essential for efficient influenza virus propagation. Embo J 2003, 22, 2717–2728. [Google Scholar] [CrossRef]
  53. Munger, J.; Hagglund, R.; Roizman, B. Infected cell protein No. 22 is subject to proteolytic cleavage by caspases activated by a mutant that induces apoptosis. Virology 2003, 305, 364–370. [Google Scholar] [CrossRef]
  54. Reed, J.C. Mechanisms of Bcl-2 family protein function and dysfunction in health and disease. Behring Institute Mitteilungen 1996, 72–100. [Google Scholar]
  55. Munger, J.; Roizman, B. The US3 protein kinase of herpes simplex virus 1 mediates the posttranslational modification of BAD and prevents BAD-induced programmed cell death in the absence of other viral proteins. Proc Natl Acad Sci U S A 2001, 98, 10410–10415. [Google Scholar] [CrossRef]
  56. Ogg, P.D.; McDonell, P.J.; Ryckman, B.J.; Knudson, C.M.; Roller, R.J. The HSV-1 Us3 protein kinase is sufficient to block apoptosis induced by overexpression of a variety of Bcl-2 family members. Virology 2004, 319, 212–224. [Google Scholar] [CrossRef]
  57. Cartier, A.; Komai, T.; Masucci, M.G. The Us3 protein kinase of herpes simplex virus 1 blocks apoptosis and induces phosporylation of the Bcl-2 family member Bad. Exp Cell Res 2003, 291, 242–250. [Google Scholar] [CrossRef]
  58. Sciortino, M.T.; Perri, D.; Medici, M.A.; Grelli, S.; Serafino, A.; Borner, C.; Mastino, A. Role of Bcl-2 expression for productive herpes simplex virus 2 replication. Virology 2006, 356, 136–146. [Google Scholar] [CrossRef]
  59. Liou, H.C. Regulation of the immune system by NF-kappaB and IkappaB. J Biochem Mol Bio 2002, 35, 537–546. [Google Scholar] [CrossRef]
  60. Chen, Z.J.; Parent, L.; Maniatis, T. Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell 1996, 84, 853–862. [Google Scholar] [CrossRef]
  61. Ghosh, S.; Baltimore, D. Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature 1990, 344, 678–682. [Google Scholar] [CrossRef]
  62. Pahl, H.L. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 1999, 18, 6853–6866. [Google Scholar] [CrossRef]
  63. Wang, C.Y.; Mayo, M.W.; Korneluk, R.G.; Goeddel, D.V.; Baldwin Jr., A.S. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 1998, 281, 1680–1683. [Google Scholar] [CrossRef]
  64. Patel, A.; Hanson, J.; McLean, T.I.; Olgiate, J.; Hilton, M.; Miller, W.E.; Bachenheimer, S.L. Herpes simplex type 1 induction of persistent NF-kappa B nuclear translocation increases the efficiency of virus replication. Virology 1998, 247, 212–222. [Google Scholar] [CrossRef]
  65. Goodkin, M.L.; Ting, A.T.; Blaho, J.A. NF-kappaB is required for apoptosis prevention during herpes simplex virus type 1 infection. J Virol 2003, 77, 7261–7280. [Google Scholar] [CrossRef]
  66. Gregory, D.; Hargett, D.; Holmes, D.; Money, E.; Bachenheimer, S.L. Efficient replication by herpes simplex virus type 1 involves activation of the IkappaB kinase-IkappaB-p65 pathway. J Virol 2004, 78, 13582–13590. [Google Scholar] [CrossRef]
  67. Medici, M.A.; Sciortino, M.T.; Perri, D.; Amici, C.; Avitabile, E.; Ciotti, M.; Balestrieri, E.; De Smaele, E.; Franzoso, G.; Mastino, A. Protection by herpes simplex virus glycoprotein D against Fas-mediated apoptosis: role of nuclear factor kappaB. J Biol Chem 2003, 278, 36059–36067. [Google Scholar] [CrossRef]
  68. Taddeo, B.; Luo, T.R.; Zhang, W.; Roizman, B. Activation of NF-kappaB in cells productively infected with HSV-1 depends on activated protein kinase R and plays no apparent role in blocking apoptosis. Proc Natl Acad Sci U S A 2003, 100, 12408–12413. [Google Scholar] [CrossRef]
  69. Taddeo, B.; Zhang, W.; Lakeman, F.; Roizman, B. Cells lacking NF-kappaB or in which NF-kappaB is not activated vary with respect to ability to sustain herpes simplex virus 1 replication and are not susceptible to apoptosis induced by a replication-incompetent mutant virus. J Virol 2004, 78, 11615–11621. [Google Scholar] [CrossRef]
  70. Yedowitz, J.C.; Blaho, J.A. Herpes simplex virus 2 modulates apoptosis and stimulates NF-kappaB nuclear translocation during infection in human epithelial HEp-2 cells. Virology 2005, 342, 297–310. [Google Scholar] [CrossRef]
  71. Goodkin, M.L.; Epstein, S.; Asbell, P.A.; Blaho, J.A. Nuclear translocation of NF-kappaB precedes apoptotic poly(ADP-ribose) polymerase cleavage during productive HSV-1 replication in corneal epithelial cells. Invest Ophthalmol vis Sci 2007, 48, 4980–4988. [Google Scholar] [CrossRef]
  72. Morton, E.R.; Blaho, J.A. Herpes simplex virus blocks Fas-mediated apoptosis independent of viral activation of NF-kappaB in human epithelial HEp-2 cells. J Interferon Cytokine Res 2007, 27, 365–376. [Google Scholar] [CrossRef]
  73. Nguyen, M.L.; Kraft, R.M.; Blaho, J.A. African green monkey kidney Vero cells require de novo protein synthesis for efficient herpes simplex virus 1-dependent apoptosis. Virology 2005, 336, 274–290. [Google Scholar] [CrossRef]
  74. Goodwin, E.C.; DiMaio, D. Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc Natl Acad Sci U S A 2000, 97, 12513–12518. [Google Scholar] [CrossRef]
  75. Nishimura, A.; Ono, T.; Ishimoto, A.; Dowhanick, J.J.; Frizzell, M.A.; Howley, P.M.; Sakai, H. Mechanisms of human papillomavirus E2-mediated repression of viral oncogene expression and cervical cancer cell growth inhibition. J Virol 2000, 74, 3752–3760. [Google Scholar] [CrossRef]
  76. Lee, C.J.; Suh, E.J.; Kang, H.T.; Im, J.S.; Um, S.J.; Park, J.S.; Hwang, E.S. Induction of senescence-like state and suppression of telomerase activity through inhibition of HPV E6/E7 gene expression in cells immortalized by HPV16 DNA. Exp Cell Res 2002, 277, 173–182. [Google Scholar] [CrossRef]
  77. Psyrri, A.; DeFilippis, R.A.; Edwards, A.P.; Yates, K.E.; Manuelidis, L.; DiMaio, D. Role of the retinoblastoma pathway in senescence triggered by repression of the human papillomavirus E7 protein in cervical carcinoma cells. Cancer Res 2004, 64, 3079–3086. [Google Scholar] [CrossRef]
  78. Horner, S.M.; DeFilippis, R.A.; Manuelidis, L.; DiMaio, D. Repression of the human papillomavirus E6 gene initiates p53-dependent, telomerase-independent senescence and apoptosis in HeLa cervical carcinoma cells. J Virol 2004, 78, 4063–4073. [Google Scholar] [CrossRef]
  79. Goodwin, E.C.; DiMaio, D. Induced senescence in HeLa cervical carcinoma cells containing elevated telomerase activity and extended telomeres. Cell Growth Differ 2001, 12, 525–534. [Google Scholar]
  80. Nguyen, M.L.; Kraft, R.M.; Aubert, M.; Goodwin, E.; DiMaio, D.; Blaho, J.A. p53 and hTERT determine sensitivity to viral apoptosis. J Virol 2007, 81, 12985–12995. [Google Scholar] [CrossRef]
  81. Munger, K.; Baldwin, A.; Edwards, K.M.; Hayakawa, H.; Nguyen, C.L.; Owens, M.; Grace, M.; Huh, K. Mechanisms of human papillomavirus-induced oncogenesis. J Virol 2004, 78, 11451–11460. [Google Scholar] [CrossRef]
  82. Lane, D.P. Cancer. p53, guardian of the genome. Nature 1992, 358, 15–16. [Google Scholar] [CrossRef]
  83. Huibregtse, J.M.; Scheffner, M.; Howley, P.M. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. Embo J 1991, 10, 4129–4135. [Google Scholar]
  84. Huibregtse, J.M.; Scheffner, M.; Howley, P.M. Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. Mol Cell Biol 1993, 13, 4918–4927. [Google Scholar]
  85. Hachiya, M.; Chumakov, A.; Miller, C.W.; Akashi, M.; Said, J.; Koeffler, H.P. Mutant p53 proteins behave in a dominant, negative fashion in vivo. Anticancer Res 1994, 14, 1853–1859. [Google Scholar]
  86. Shaulian, E.; Zauberman, A.; Ginsberg, D.; Oren, M. Identification of a minimal transforming domain of p53: negative dominance through abrogation of sequence-specific DNA binding. Mol Cell Biol 1992, 12, 5581–5592. [Google Scholar]
  87. Boutell, C.; Everett, R.D. The herpes simplex virus type 1 (HSV-1) regulatory protein ICP0 interacts with and Ubiquitinates p53. J Biol Chem 2003, 278, 36596–36602. [Google Scholar] [CrossRef]
  88. Boutell, C.; Everett, R.D. Herpes simplex virus type 1 infection induces the stabilization of p53 in a USP7- and ATM-independent manner. J Virol 2004, 78, 8068–8077. [Google Scholar] [CrossRef]
  89. Hobbs 2nd, W.E.; DeLuca, N.A. Perturbation of cell cycle progression and cellular gene expression as a function of herpes simplex virus ICP0. J Virol 1999, 73, 8245–8255. [Google Scholar]
  90. Harrington, L.; Zhou, W.; McPhail, T.; Oulton, R.; Yeung, D.S.; Mar, V.; Bass, M.B.; Robinson, M.O. Human telomerase contains evolutionarily conserved catalytic and structural subunits. Genes & development 1997, 11, 3109–3115. [Google Scholar] [CrossRef]
  91. Kilian, A.; Bowtell, D.D.; Abud, H.E.; Hime, G.R.; Venter, D.J.; Keese, P.K.; Duncan, E.L.; Reddel, R.R.; Jefferson, R.A. Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types. Hum Mol Genet 1997, 6, 2011–2019. [Google Scholar] [CrossRef]
  92. Meyerson, M.; Counter, C.M.; Eaton, E.N.; Ellisen, L.W.; Steiner, P.; Caddle, S.D.; Ziaugra, L.; Beijersbergen, R.L.; Davidoff, M.J.; Liu, Q.; Bacchetti, S.; Haber, D.A.; Weinberg, R.A. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 1997, 90, 785–795. [Google Scholar] [CrossRef]
  93. Nakamura, T.M.; Morin, G.B.; Chapman, K.B.; Weinrich, S.L.; Andrews, W.H.; Lingner, J.; Harley, C.B.; Cech, T.R. Telomerase catalytic subunit homologs from fission yeast and human. Science 1997, 277, 955–959. [Google Scholar] [CrossRef]
  94. Greider, C.W.; Blackburn, E.H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 1985, 43, 405–413. [Google Scholar] [CrossRef]
  95. de Lange, T.; Shiue, L.; Myers, R.M.; Cox, D.R.; Naylor, S.L.; Killery, A.M.; Varmus, H.E. Structure and variability of human chromosome ends. Mol Cell Biol 1990, 10, 518–527. [Google Scholar]
  96. Harley, C.B.; Futcher, A.B.; Greider, C.W. Telomeres shorten during ageing of human fibroblasts. Nature 1990, 345, 458–460. [Google Scholar] [CrossRef]
  97. Hastie, N.D.; Dempster, M.; Dunlop, M.G.; Thompson, A.M.; Green, D.K.; Allshire, R.C. Telomere reduction in human colorectal carcinoma and with ageing. Nature 1990, 346, 866–868. [Google Scholar] [CrossRef]
  98. Harley, C.B.; Kim, N.W.; Prowse, K.R.; Weinrich, S.L.; Hirsch, K.S.; West, M.D.; Bacchetti, S.; Hirte, H.W.; Counter, C.M.; Greider, C.W.; et al. Telomerase, cell immortality, and cancer. Cold Spring Harbor Symp Quant Biol 1994, 59, 307–31. [Google Scholar]
  99. Klingelhutz, A.J.; Foster, S.A.; McDougall, J.K. Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature 1996, 380, 79–82. [Google Scholar] [CrossRef]
  100. Akiyama, M.; Yamada, O.; Kanda, N.; Akita, S.; Kawano, T.; Ohno, T.; Mizoguchi, H.; Eto, Y.; Anderson, K.C.; Yamada, H. Telomerase overexpression in K562 leukemia cells protects against apoptosis by serum deprivation and double-stranded DNA break inducing agents, but not against DNA synthesis inhibitors. Cancer letters 2002, 178, 187–197. [Google Scholar] [CrossRef]
  101. Luiten, R.M.; Pene, J.; Yssel, H.; Spits, H. Ectopic hTERT expression extends the life span of human CD4+ helper and regulatory T-cell clones and confers resistance to oxidative stress-induced apoptosis. Blood 2003, 101, 4512–4519. [Google Scholar] [CrossRef]
  102. Ren, J.G.; Xia, H.L.; Tian, Y.M.; Just, T.; Cai, G.P.; Dai, Y.R. Expression of telomerase inhibits hydroxyl radical-induced apoptosis in normal telomerase negative human lung fibroblasts. FEBS letters 2001, 488, 133–138. [Google Scholar] [CrossRef]
  103. Yuan, Z.; Mei, H.D. Inhibition of telomerase activity with hTERT antisense increases the effect of CDDP-induced apoptosis in myeloid leukemia. Hematol J 2002, 3, 201–205. [Google Scholar] [CrossRef]
Viruses EISSN 1999-4915 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert