p53 Is Regulated in a Biphasic Manner in Hypoxic Human Papillomavirus Type 16 (HPV16)-Positive Cervical Cancer Cells
Abstract
:1. Introduction
2. Results
2.1. p53 Is Regulated in a Biphasic Manner in Hypoxic E6/E7-Repressed HPV16-Positive Cervical Cancer Cells
2.2. Lysosomal Degradation Is Required for the Initial Reduction of p53 in Hypoxic Cells
2.3. Hypoxic HPV16-Positive Cancer Cells Do Not Enter Senescence
2.4. p53-Responsive Genes Associated with Autophagy Are Induced in Hypoxic Cells
2.5. The Evasion of Hypoxic HPV16-Positive Cancer Cells from Senescence Can Be Attributed to the Induction of Autophagy
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Treatment of Cells with Chemical Compounds
4.3. siRNA Transfection
4.4. Ectopic Expression of p53
4.5. Protein Extraction and Western Blotting
4.6. RNA Extraction and Reverse Transcription
4.7. Quantitative Real-Time PCR Analyses
4.8. Cycloheximide (CHX) Treatment under Normoxic and Hypoxic Conditions
4.9. Senescence Assays
4.10. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
BafA1 | bafilomycin A1 |
CHX | cycloheximide |
CQ | chloroquine |
HPV | human papillomavirus |
References
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, A.L.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [Green Version]
- Walboomers, J.M.; Jacobs, M.V.; Manos, M.M.; Bosch, F.X.; Kummer, J.A.; Shah, K.V.; Snijders, P.J.; Peto, J.; Meijer, C.J.; Munoz, V. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J. Pathol. 1999, 189, 12–19. [Google Scholar] [CrossRef]
- Moody, C.A.; Laimins, L.A. Human papillomavirus oncoproteins: Pathways to transformation. Nat. Rev. Cancer 2010, 10, 550–560. [Google Scholar] [CrossRef] [PubMed]
- Brisson, M.; Benard, E.; Drolet, M.; Bogaards, J.A.; Baussano, I.; Vanska, S.; Jit, M.; Boily, M.C.; Smith, M.A.; Berkhof, J.; et al. Population-level impact, herd immunity, and elimination after human papillomavirus vaccination: A systematic review and meta-analysis of predictions from transmission-dynamic models. Lancet Public Health 2016, 1, e8–e17. [Google Scholar] [CrossRef] [Green Version]
- Castle, P.E.; Maza, M. Prophylactic HPV vaccination: Past, present, and future. Epidemiol. Infect. 2016, 144, 449–468. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wabinga, H.R.; Nambooze, S.; Amulen, P.M.; Okello, C.; Mbus, L.; Parkin, D.M. Trends in the incidence of cancer in Kampala, Uganda 1991–2010. Int. J. Cancer 2014, 135, 432–439. [Google Scholar] [CrossRef] [PubMed]
- Chokunonga, E.; Borok, M.Z.; Chirenje, Z.M.; Nyakabau, A.M.; Parkin, D.M. Trends in the incidence of cancer in the black population of Harare, Zimbabwe 1991–2010. Int. J. Cancer 2013, 133, 721–729. [Google Scholar] [CrossRef]
- Bray, F.; Lortet, T.J.; Znaor, A.; Brotons, M.; Poljak, M.; Arbyn, M. Patterns and trends in human papillomavirus-related diseases in Central and Eastern Europe and Central Asia. Vaccine 2013, 31 (Suppl. 7), H32–H45. [Google Scholar] [CrossRef]
- World Health Organization. World Health Organization Comprehensive Cervical Cancer Control: A Guide to Essential Practice, 2nd ed.; World Health Organization: Geneva, Switzerland, 2014. [Google Scholar]
- Chuang, L.T.; Temin, S.; Camacho, R.; Duenas-Gonzalez, A.; Feldman, S.; Gultekin, M.; Gupta, V.; Horton, S.; Jacob, G.; Kidd, E.A.; et al. Management and Care of Women With Invasive Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Clinical Practice Guideline. J. Glob. Oncol. 2016, 2, 311–340. [Google Scholar] [CrossRef]
- Ke, G.; Liang, L.; Yang, J.M.; Huang, X.; Han, D.; Huang, S.; Zhao, Y.; Zha, R.; He, X.; Wu, X. MiR-181a confers resistance of cervical cancer to radiation therapy through targeting the pro-apoptotic PRKCD gene. Oncogene 2013, 32, 3019–3027. [Google Scholar] [CrossRef] [Green Version]
- Zhu, H.; Luo, H.; Zhang, W.; Shen, Z.; Hu, X.; Zhu, X. Molecular mechanisms of cisplatin resistance in cervical cancer. Drug Des. Devel. Ther. 2016, 10, 1885–1895. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vaupel, P.; Mayer, A. Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev. 2007, 26, 225–239. [Google Scholar] [CrossRef] [PubMed]
- Hockel, M.; Vaupel, P. Tumor hypoxia: Definitions and current clinical, biologic, and molecular aspects. J. Natl. Cancer Inst. 2001, 93, 266–276. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vaupel, P.; Harrison, L. Tumor hypoxia: Causative factors, compensatory mechanisms, and cellular response. Oncologist 2004, 9 (Suppl. 5), 4–9. [Google Scholar] [CrossRef] [Green Version]
- Vaupel, P.; Thews, O.; Hoeckel, M. Treatment resistance of solid tumors: Role of hypoxia and anemia. Med. Oncol. 2001, 18, 243–259. [Google Scholar] [CrossRef]
- Bachtiary, B.; Schindl, M.; Potter, R.; Dreier, B.; Knocke, T.H.; Hainfellner, J.A.; Horvat, R.; Birner, P. Overexpression of hypoxia-inducible factor 1alpha indicates diminished response to radiotherapy and unfavorable prognosis in patients receiving radical radiotherapy for cervical cancer. Clin. Cancer Res. 2003, 9, 2234–2240. [Google Scholar]
- Birner, P.; Schindl, M.; Obermair, A.; Plank, C.; Breitenecker, G.; Oberhuber, G. Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res. 2000, 60, 4693–4696. [Google Scholar]
- Sorensen, B.S.; Busk, M.; Olthof, N.; Speel, E.J.; Horsman, M.R.; Alsner, J.; Overgaard, J. Radiosensitivity and effect of hypoxia in HPV positive head and neck cancer cells. Radiother. Onco. 2013, 108, 500–505. [Google Scholar] [CrossRef]
- Iwasaki, K.; Yabushita, H.; Ueno, T.; Wakatsuki, A. Role of hypoxia-inducible factor-1alpha, carbonic anhydrase-IX, glucose transporter-1 and vascular endothelial growth factor associated with lymph node metastasis and recurrence in patients with locally advanced cervical cancer. Oncol. Lett. 2015, 10, 1970–1978. [Google Scholar] [CrossRef] [Green Version]
- Hoppe-Seyler, K.; Bossler, F.; Lohrey, C.; Bulkescher, J.; Rosl, F.; Jansen, L.; Mayer, A.; Vaupel, P.; Durst, M.; Hoppe-Seyler, F. Induction of dormancy in hypoxic human papillomavirus-positive cancer cells. Proc. Natl. Acad. Sci. USA 2017, 114, E990–E998. [Google Scholar] [CrossRef] [Green Version]
- Kim, C.Y.; Tsai, M.H.; Osmanian, C.; Graeber, T.G.; Lee, J.E.; Giffard, R.G.; DiPaolo, J.A.; Peehl, D.M.; Giaccia, A.J. Selection of human cervical epithelial cells that possess reduced apoptotic potential to low-oxygen conditions. Cancer Res. 1997, 57, 4200–4204. [Google Scholar] [PubMed]
- Levine, A.J. p53, the cellular gatekeeper for growth and division. Cell 1997, 88, 323–331. [Google Scholar] [CrossRef] [Green Version]
- Lee, S.; Elenbaas, B.; Levine, A.; Griffith, J. p53 and its 14 kDa C-terminal domain recognize primary DNA damage in the form of insertion/deletion mismatches. Cell 1995, 81, 1013–1020. [Google Scholar] [CrossRef] [Green Version]
- el-Deiry, W.S.; Tokino, T.; Velculescu, V.E.; Levy, D.B.; Parsons, R.; Trent, J.M.; Lin, D.; Mercer, W.E.; Kinzler, K.W.; Vogelstein, B. WAF1, a potential mediator of p53 tumor suppression. Cell 1993, 75, 817–825. [Google Scholar] [CrossRef]
- Lowe, S.W.; Ruley, H.E.; Jacks, T.; Housman, D.E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993, 74, 957–967. [Google Scholar] [CrossRef]
- 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] [PubMed] [Green Version]
- Maiuri, M.C.; Galluzzi, L.; Morselli, E.; Kepp, O.; Malik, S.A.; Kroemer, G. Autophagy regulation by p53. Curr. Opin. Cell Biol. 2010, 22, 181–185. [Google Scholar] [CrossRef] [PubMed]
- Gottlieb, E.; Vousden, K.H. p53 regulation of metabolic pathways. Cold Spring Harb. Perspect. Biol. 2010, 2, a001040. [Google Scholar] [CrossRef] [Green Version]
- Kruse, J.P.; Gu, W. Modes of p53 regulation. Cell 2009, 137, 609–622. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Scheffner, M.; Huibregtse, J.M.; Vierstra, R.D.; Howley, P.M. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993, 75, 495–505. [Google Scholar] [CrossRef]
- Martinez-Zapien, D.; Ruiz, F.X.; Poirson, J.; Mitschler, A.; Ramirez, J.; Forster, A.; Cousido-Siah, A.; Masson, M.; Vande Pol, S.; Podjarny, A.; et al. Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature 2016, 529, 541–545. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, C.; Johnson, D.E. Liberation of functional p53 by proteasome inhibition in human papilloma virus-positive head and neck squamous cell carcinoma cells promotes apoptosis and cell cycle arrest. Cell Cycle 2013, 12, 923–934. [Google Scholar] [CrossRef] [PubMed]
- Vaupel, P.; Hockel, M.; Mayer, A. Detection and characterization of tumor hypoxia using p O2 histography. Antioxid. Redox Signal 2007, 9, 1221–1235. [Google Scholar] [CrossRef] [PubMed]
- Alarcon, R.; Koumenis, C.; Geyer, R.K.; Maki, C.G.; Giaccia, A.J. Hypoxia induces p53 accumulation through MDM2 down-regulation and inhibition of E6-mediated degradation. Cancer Res. 1999, 59, 6046–6051. [Google Scholar]
- Rodriguez, J.; Herrero, A.; Li, S.; Rauch, N.; Quintanilla, A.; Wynne, K.; Krstic, A.; Acosta, J.C.; Taylor, C.; Schlisio, S.; et al. PHD3 Regulates p53 Protein Stability by Hydroxylating Proline 359. Cell Rep. 2018, 24, 1316–1329. [Google Scholar] [CrossRef] [Green Version]
- Oladipupo, S.; Hu, S.; Kovalski, J.; Yao, J.; Santeford, A.; Sohn, R.E.; Shohet, R.; Maslov, K.; Wang, L.V.; Arbeit, J.M. VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting. Proc. Natl. Acad. Sci. USA 2011, 108, 13264–13269. [Google Scholar] [CrossRef] [Green Version]
- Obrig, T.G.; Culp, W.J.; McKeehan, W.L.; Hardesty, B. The mechanism by which cycloheximide and related glutarimide antibiotics inhibit peptide synthesis on reticulocyte ribosomes. J. Biol. Chem. 1971, 246, 174–181. [Google Scholar]
- Michael, D.; Oren, M. The p53-Mdm2 module and the ubiquitin system. Semin. Cancer Biol. 2003, 13, 49–58. [Google Scholar] [CrossRef]
- Hengstermann, A.; Linares, L.K.; Ciechanover, A.; Whitaker, N.J.; Scheffner, M. Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells. Proc. Natl. Acad. Sci. USA 2001, 98, 1218–1223. [Google Scholar] [CrossRef]
- Moll, U.M.; Petrenko, O. The MDM2-p53 interaction. Mol. Cancer Res. 2003, 1, 1001–1008. [Google Scholar]
- Lee, D.H.; Goldberg, A.L. Proteasome inhibitors: Valuable new tools for cell biologists. Trends. Cell Biol. 1998, 8, 397–403. [Google Scholar] [CrossRef]
- Kobayashi, S. Choose Delicately and Reuse Adequately: The Newly Revealed Process. of Autophagy. Biol. Pharm. Bull. 2015, 38, 1098–1103. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yucel, L.T.; Jansson, H.; Glaumann, H. Proteolysis in isolated autophagic vacuoles from the rat pancreas. Effects of chloroquine administration. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 1991, 61, 141–145. [Google Scholar] [CrossRef] [PubMed]
- Yamamoto, A.; Tagawa, Y.; Yoshimori, T.; Moriyama, Y.; Masaki, R.; Tashiro, Y. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct. Funct. 1998, 23, 33–42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pankiv, S.; Clausen, T.H.; Lamark, T.; Brech, A.; Bruun, J.A.; Outzen, H.; Overvatn, A.; Bjorkoy, G.; Johansen, T. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 2007, 282, 24131–24145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pursiheimo, J.P.; Rantanen, K.; Heikkinen, P.T.; Johansen, T.; Jaakkola, P.M. Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62. Oncogene 2009, 28, 334–344. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Goodwin, E.C.; Yang, E.; Lee, C.J.; Lee, H.W.; DiMaio, D.; Hwang, E.S. Rapid induction of senescence in human cervical carcinoma cells. Proc. Natl. Acad. Sci. USA 2000, 97, 10978–10983. [Google Scholar] [CrossRef] [Green Version]
- de Stanchina, E.; Querido, E.; Narita, M.; Davuluri, R.V.; Pandolfi, P.P.; Ferbeyre, G.; Lowe, S.W. PML is a direct p53 target that modulates p53 effector functions. Mol. Cell 2004, 13, 523–535. [Google Scholar] [CrossRef] [Green Version]
- Kelley, K.D.; Miller, K.R.; Todd, A.; Kelley, A.R.; Tuttle, R.; Berberich, S.J. YPEL3, a p53-regulated gene that induces cellular senescence. Cancer Res. 2010, 70, 3566–3575. [Google Scholar] [CrossRef] [Green Version]
- Dimri, G.P.; Lee, X.; Basile, G.; Acosta, M.; Scott, G.; Roskelley, C.; Medrano, E.E.; Linskens, M.; Rubelj, I.; Pereira-Smith, O.; et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. USA 1995, 92, 9363–9367. [Google Scholar] [CrossRef] [Green Version]
- Riley, T.; Sontag, E.; Chen, P.; Levine, A. Transcriptional control of human p53-regulated genes. Nat. Rev. Mol. Cell Biol. 2008, 9, 402–412. [Google Scholar] [CrossRef]
- Wang, Q.E.; Zhu, Q.; Wani, M.A.; Wani, G.; Chen, J.; Wani, A.A. Tumor suppressor p53 dependent recruitment of nucleotide excision repair factors XPC and TFIIH to DNA damage. DNA Repair 2003, 2, 483–499. [Google Scholar] [CrossRef]
- Salvador, J.M.; Brown, C.J.D.; Fornace, A.J., Jr. Gadd45 in stress signaling, cell cycle control, and apoptosis. Adv. Exp. Med. Biol. 2013, 793, 1–19. [Google Scholar] [PubMed]
- Niehrs, C.; Schafer, A. Active DNA demethylation by Gadd45 and DNA repair. Trends. Cell Biol. 2012, 22, 220–227. [Google Scholar] [CrossRef] [PubMed]
- Crighton, D.; Wilkinson, S.; O’Prey, J.; Syed, N.; Smith, P.; Harrison, P.R.; Gasco, M.; Garrone, O.; Crook, T.; Ryan, K.M. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 2006, 126, 121–134. [Google Scholar] [CrossRef] [Green Version]
- Tracy, K.; Dibling, B.C.; Spike, B.T.; Knabb, J.R.; Schumacker, P.; Macleod, K.F. BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol. Cell Bio. 2007, 27, 6229–6242. [Google Scholar] [CrossRef] [Green Version]
- Green, D.R.; Chipuk, J.E. p53 and metabolism: Inside the TIGAR. Cell 2006, 126, 30–32. [Google Scholar] [CrossRef] [Green Version]
- Shimizu, T.; Sugihara, E.; Yamaguchi-Iwai, S.; Tamaki, S.; Koyama, Y.; Kamel, W.; Ueki, A.; Ishikawa, T.; Chiyoda, T.; Osuka, S.; et al. IGF2 preserves osteosarcoma cell survival by creating an autophagic state of dormancy that protects cells against chemotherapeutic stress. Cancer Res. 2014, 74, 6531–6541. [Google Scholar] [CrossRef] [Green Version]
- Chaterjee, M.; van Golen, K.L. Breast cancer stem cells survive periods of farnesyl-transferase inhibitor-induced dormancy by undergoing autophagy. Bone Marrow Res. 2011, 2011, 362938. [Google Scholar] [CrossRef] [Green Version]
- Rouschop, K.M.; Wouters, B.G. Regulation of autophagy through multiple independent hypoxic signaling pathways. Curr. Mol. Med. 2009, 9, 417–424. [Google Scholar] [CrossRef]
- Kurz, D.J.; Decary, S.; Hong, Y.; Erusalimsky, J.D. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J. Cell. Sci. 2000, 113 Pt 20, 3613–3622. [Google Scholar] [PubMed]
- White, E. Autophagy and p53. Cold Spring Harb. Perspect. Med. 2016, 6, a026120. [Google Scholar] [CrossRef] [PubMed]
- Linder, B.; Kogel, D. Autophagy in Cancer Cell Death. Biology 2019, 8, 82. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Campillo, N.; Falcones, B.; Otero, J.; Colina, R.; Gozal, D.; Navajas, D.; Farre, R.; Almendros, I. Differential Oxygenation in Tumor Microenvironment Modulates Macrophage and Cancer Cell Crosstalk: Novel Experimental Setting and Proof of Concept. Front. Oncol. 2019, 9, 43. [Google Scholar] [CrossRef] [Green Version]
- Gillies, R.J.; Brown, J.S.; Anderson, A.R.A.; Gatenby, R.A. Eco-evolutionary causes and consequences of temporal changes in intratumoural blood flow. Nat. Rev. Cancer. 2018, 18, 576–585. [Google Scholar] [CrossRef]
- Bhandari, V.; Hoey, C.; Liu, L.Y.; Lalonde, E.; Ray, J.; Livingstone, J.; Lesurf, R.; Shiah, Y.J.; Vujcic, T.; Huang, X.; et al. Molecular landmarks of tumor hypoxia across cancer types. Nat. Genet. 2019, 51, 308–318. [Google Scholar] [CrossRef]
- Humpton, T.J.; Vousden, K.H. Regulation of Cellular Metabolism and Hypoxia by p53. Cold Spring Harb. Perspect. Med. 2016, 6, a026146. [Google Scholar] [CrossRef] [Green Version]
- Al Tameemi, W.; Dale, T.P.; Al-Jumaily, R.M.K.; Forsyth, N.R. Hypoxia-Modified Cancer Cell Metabolism. Front. Cell Dev. Biol. 2019, 7, 4. [Google Scholar] [CrossRef] [Green Version]
- Walton, Z.E.; Patel, C.H.; Brooks, R.C.; Yu, Y.; Ibrahim-Hashim, A.; Riddle, M.; Porcu, A.; Jiang, T.; Ecker, B.L.; Tameire, F.; et al. Acid Suspends the Circadian Clock in Hypoxia through Inhibition of mTOR. Cell 2018, 174, 72–87.e32. [Google Scholar] [CrossRef] [Green Version]
- Lai, M.C.; Chang, C.M.; Sun, H.S. Hypoxia Induces Autophagy through Translational Up-Regulation of Lysosomal Proteins in Human Colon Cancer Cells. PLoS ONE 2016, 11, e0153627. [Google Scholar] [CrossRef] [Green Version]
- Scherz-Shouval, R.; Weidberg, H.; Gonen, C.; Wilder, S.; Elazar, Z.; Oren, M. p53-dependent regulation of autophagy protein LC3 supports cancer cell survival under prolonged starvation. Proc. Natl. Acad. Sci. USA 2010, 107, 18511–18516. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Loos, B.; du Toit, A.; Hofmeyr, J.H. Defining and measuring autophagosome flux-concept and reality. Autophagy 2014, 10, 2087–2096. [Google Scholar] [CrossRef] [PubMed]
- Bhutia, S.K.; Mukhopadhyay, S.; Sinha, N.; Das, D.N.; Panda, P.K.; Patra, S.K.; Maiti, T.K.; Mandal, M.; Dent, P.; Wang, X.Y.; et al. Autophagy: Cancer’s friend or foe? Adv. Cancer Res. 2013, 118, 61–95. [Google Scholar] [PubMed]
- Perez-Hernandez, M.; Arias, A.; Martinez-Garcia, D.; Perez-Tomas, R.; Quesada, R.; Soto-Cerrato, V. Targeting Autophagy for Cancer Treatment and Tumor Chemosensitization. Cancers 2019, 11, 1599. [Google Scholar] [CrossRef] [Green Version]
- Bodelon, C.; Vinokurova, S.; Sampson, J.N.; den Boon, J.A.; Walker, J.L.; Horswill, M.A.; Korthauer, K.; Schiffman, M.; Sherman, M.E.; Zuna, R.E.; et al. Chromosomal copy number alterations and HPV integration in cervical precancer and invasive cancer. Carcinogenesis 2016, 37, 188–196. [Google Scholar] [CrossRef] [Green Version]
- Dong, X.; Huang, D.; Yi, X.; Zhang, S.; Wang, Z.; Yan, B.; Chung Sham, P.; Chen, K.; Jun Li, M. Diversity spectrum analysis identifies mutation-specific effects of cancer driver genes. Commun. Biol. 2020, 3, 6. [Google Scholar] [CrossRef] [Green Version]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Zhuang, L.; Ly, R.; Rösl, F.; Niebler, M. p53 Is Regulated in a Biphasic Manner in Hypoxic Human Papillomavirus Type 16 (HPV16)-Positive Cervical Cancer Cells. Int. J. Mol. Sci. 2020, 21, 9533. https://doi.org/10.3390/ijms21249533
Zhuang L, Ly R, Rösl F, Niebler M. p53 Is Regulated in a Biphasic Manner in Hypoxic Human Papillomavirus Type 16 (HPV16)-Positive Cervical Cancer Cells. International Journal of Molecular Sciences. 2020; 21(24):9533. https://doi.org/10.3390/ijms21249533
Chicago/Turabian StyleZhuang, Linhan, Regina Ly, Frank Rösl, and Martina Niebler. 2020. "p53 Is Regulated in a Biphasic Manner in Hypoxic Human Papillomavirus Type 16 (HPV16)-Positive Cervical Cancer Cells" International Journal of Molecular Sciences 21, no. 24: 9533. https://doi.org/10.3390/ijms21249533