Search Results (61)

Transcription factors (TFs) are proteins that control gene expression by binding to specific DNA sequences and are essential for cell development, differentiation, and homeostasis. Dysregulation of TFs is implicated in numerous diseases, including cancer, autoimmune disorders, and neurodegeneration. While TFs were traditionally considered “undruggable” due to their lack of well-defined binding pockets, recent advances have made it possible to modulate their activity using diverse pharmacological strategies. Major TF families include NF-κB, p53, STATs, HIF-1α, AP-1, Nrf2, and nuclear hormone receptors, which take part in the regulation of inflammation, tumor suppression, cytokine signaling, hypoxia and stress response, oxidative stress, and hormonal response, respectively. TFs can perform multiple functions, participating in the regulation of opposing processes depending on the context. NF-κB, for instance, plays dual roles in immunity and cancer, and is targeted by proteasome and IKKβ inhibitors. p53, often mutated in cancer, is reactivated using MDM2 antagonist Nutlin-3, refunctionalizing compound APR-246, or stapled peptides. HIF-1α, which regulates hypoxic responses and angiogenesis, is inhibited by agents like acriflavine or stabilized in anemia therapies by HIF-PHD inhibitor roxadustat. STATs, especially STAT3 and STAT5, are oncogenic and targeted via JAK inhibitors or novel PROTAC degraders, for instance SD-36. AP-1, implicated in cancer and arthritis, can be inhibited by T-5224 or kinase inhibitors JNK and p38 MAPK. Nrf2, a key antioxidant regulator, can be activated by agents like DMF or inhibited in chemoresistant tumors. Pharmacological strategies include direct inhibitors, activators, PROTACs, molecular glues, and epigenetic modulators. Challenges remain, including the structural inaccessibility of TFs, functional redundancy, off-target effects, and delivery barriers. Despite these challenges, transcription factor modulation is emerging as a viable and promising therapeutic approach, with ongoing research focusing on specificity, safety, and efficient delivery methods to realize its full clinical potential. Full article

As a major global health challenge, hepatocellular carcinoma (HCC) still faces substantial limitations in its treatment options. This study investigates the anti-HCC potential of ACY-1215, a selective Histone deacetylase 6 (HDAC6) inhibitor, and its mechanism targeting p53 regulation. In vitro studies conducted with HepG2 and SMMC-7721 cells revealed that ACY-1215 markedly inhibited HCC cell proliferation, migratory capacity, and invasive potential, as evidenced by CCK-8, colony formation, and Transwell assays. Furthermore, ACY-1215 induced caspase-dependent apoptosis. Mechanistically, ACY-1215 enhanced p53 acetylation by disrupting HDAC6-p53 interaction, thereby stabilizing p53 protein levels. Concurrently, it inhibited Murine Double Minute 2 (MDM2)-mediated ubiquitination, blocking proteasomal degradation and prolonging p53 half-life. This dual modulation restored p53 transcriptional activity, leading to the upregulation of downstream effector molecules associated with cell cycle regulation and apoptosis. Collectively, our findings reveal that ACY-1215 exerts potent anti-HCC effects through coordinated regulation of p53 acetylation and ubiquitination, offering a novel dual-targeting strategy for HCC therapy. Full article

Background: Swine hepatitis E (HEV) is a zoonotic infectious disease caused by the swine hepatitis E virus (SHEV). Open reading frame 3 (ORF3) is a key virulence factor in swine HEV, playing a crucial role in the release of viral particles, the modulation of the host innate immune response, and regulation of autophagy and apoptosis, etc. However, its main function and pathogenic mechanism remain incompletely understood. Results: In our study, adenoviruses ADV4-ORF3 and ADV4-GFP were successfully constructed and mediated the overexpression of enhanced green fluorescent protein (EGFP)-ORF3 and EGFP in HepG2 cells. A total of 217 differentially expressed messenger RNAs (mRNAs) were screened by high-throughput sequencing, and 27 statistically significant differentially expressed genes were screened for further quantitative real-time reverse transcription (qRT-PCR) verification by functional enrichment (Gene Ontology [GO] and Kyoto Encyclopedia of Genes and Genomes [KEGG]). They are mainly involved in six pathways: the cellular response to unfolded protein, inflammatory response, cytokine activity, TNF signaling pathway, influenza A, and pathways in cancer. In a comparative analysis of transcriptome and mRNA expression profiles of lncRNA sequencing, the results showed that 3 mRNAs of GPX1, MDM4, and CLDN and 39 transcripts overlapped and have been identified. Conclusions: Eight differential genes, HSPA1A, HSPA1B, PLD3, RELA, GPI, SAMHD1, RPS6KA4, and PIK3CB, were successfully verified. Comparing and analyzing the results of the two sequencing methods indicated that the 3 mRNAs of GPX1, MDM4, and CLDN and 39 transcripts overlapped and have been identified in SHEV ORF3-expressing HepG2 cells, which has laid a genetic foundation for the physiological function and mechanism of SHEV ORF3. Full article

Background: Giant cell tumor of bone (GCTB) is a locally aggressive tumor. It accounts for only 5% of all bony tumors. Early diagnosis, and follow-up for recurrence is often difficult due to a lack of biogenetic markers. Giant cells are multinucleated epithelioid cells derived from macrophages. Histologically, giant cells are also present in other pathologies of bone, e.g., aneurysmal bone cyst, chondroblastoma, giant cell granuloma, and malignant giant cell tumor, etc. Similarly, radiographic findings overlap with other osteolytic lesions, making the diagnosis and prognosis of giant cell tumor very challenging. Aims and Objectives: The purpose of this study was to explore biological and genetic markers which can be used for detection, differentiation, recurrence, and prognosis of GCTB. This will help to better understand the clinical outcome of GCTB and minimize the need for interventions. Methods: We conducted a literature search using Google, Google Scholar, PubMed, Wiley Library, Medline, Clinical trials.org, and Web of Science. Our search strategy included MeSH terms and key words for giant cell tumor and biogenetic markers from date of inception to September 2020. After excluding review articles, 246 duplicates, and non-relevant articles, we included 24 articles out of 1568 articles, summarizing the role of biogenetic markers in the prognosis of GCT. Results: P63 is 98.6% sensitive and relatively specific for GCT as compared to other multinucleated giant cells containing neoplasms. MDM2 (mouse double minute 2 homolog), IGF1 (insulin-like growth factor 1), STAT1 (signal transducer and activator of transcription 1), and RAC1 (Ras-related C3 botulinum toxin substrate 1) are associated with GCTB recurrence, and might serve as biomarkers for it. Increased expression of the proteins STAT5B, GRB2, and OXSR1 was related to a higher probability of metastasis. H3F3A and H3F3B mutation analysis appears to be a highly specific, although less sensitive, diagnostic tool for the distinction of giant cell tumor of bone (GCTB) and chondroblastoma from other giant cell-containing tumors. A neutrophil to lymphocyte ratio (NLR) > 2.70, platelet to lymphocyte ratio (PLR) > 215.80, lymphocyte to monocyte ratio (LMR) ≤ 2.80, and albumin to globulin ratio (AGR) < 1.50 were significantly associated with decreased disease-free survival (DFS) (p < 0.05). Large amounts of osteoclast-related mRNA (cathepsin K, tartrate-resistant acid phosphatase, and matrix metalloproteinase9) in GCTs (p < 0.05) are associated with the grade of bone resorption. We propose that subarticular primary malignant bone sarcomas with H3.3 mutations represent true malignant GCTB, even in the absence of a benign GCTB component. IMP3 and IGF2 might be potential biomarkers for GCT of the spine in regulating the angiogenesis of giant cell tumor of bone and predicting patients’ prognosis. Conclusions: This review study shows serological markers, genetic factors, cell membrane receptor markers, predictive markers for malignancy, and prognostic protein markers which are highly sensitive for GCT and relatively specific for giant cell tumor. MDM2, IGF1, STAT1, RAC1 are important makers in determining recurrence, while P63 and H3F3A differentiate GCT from other giant cell-containing tumors. STAT5B, GRB2, and OXSR1 are significant in determining the prognosis of GCT. Apart from using radiological and histological parameters, we can add them to tumor work-up for definitive diagnosis and prognosis. Full article

Radiotherapy remains a cornerstone in cancer treatment, leveraging ionizing radiation to eradicate malignant cells. Its efficacy, however, is frequently challenged by the heterogeneous sensitivity of tumors and surrounding tissues to radiation. Therefore, understanding the molecular mechanisms underlying radiosensitivity is crucial for improving treatment outcomes. Among the myriad of molecular players involved, the tumor suppressor protein p53 stands out as a central regulator with significant implications for radiosensitivity. Known as the “guardian of the genome”, p53 plays a pivotal role in maintaining genomic stability and orchestrating cellular responses such as cell cycle arrest, DNA repair, apoptosis, and senescence in response to various stress signals, including radiation-induced DNA damage. Activation of p53 triggers the transcription of target genes involved in DNA repair pathways, such as p21, MDM2, and GADD45, facilitating the repair of radiation-induced DNA damage or the elimination of irreparably damaged cells. This, in turn, influences the overall radiosensitivity of tissues. Mutations in the TP53 gene, which encodes p53, are among the most frequent genetic alterations in human cancers. Loss or dysfunction of p53 can compromise the cellular response to radiation, leading to increased resistance to therapy and poorer clinical outcomes. Conversely, intact p53 function is associated with enhanced radiosensitivity due to its ability to promote cell cycle arrest and apoptosis in response to radiation-induced DNA damage. In conclusion, elucidating the molecular mechanisms by which p53 influences radiosensitivity is essential for advancing our understanding of the radiation response in cancer cells and developing more effective therapeutic approaches to cancer treatment. This review provides a comprehensive overview of the multifaceted role of p53 in modulating cellular responses to radiation, emphasizing its influence on radiosensitivity. Full article

MicroRNAs are key post-transcriptional regulators of gene expression and their dysregulation is often linked to cancer. Epstein-Barr virus encodes 22 BamHI A Rightward Transcript (BART) miRNAs, which are expressed in nearly all EBV-associated cancers and implicated in viral pathogenesis. To investigate biological targets for BART miRNAs in B cell lymphomas, we performed a meta-analysis of publicly available Ago-CLIP datasets from EBV-positive Burkitt lymphomas (BLs), primary effusion lymphomas (PELs), AIDS-associated diffuse large B cell lymphomas (DLBCLs), and lymphoblastoid cell lines (LCLs). Our analysis focused on comparing targets of EBV BART miRNAs across the different types of transformed B cells. Using reporter assays, we then experimentally validated over 50 functional interactions between BART miRNAs and cellular protein-coding transcripts involved in activities such as B cell differentiation (PRDM1, IRF4, and MYC), cell cycle regulation (UHMK1, CDKN1A, MDM2, and NPAT), apoptosis (MCL1), signaling and intracellular trafficking (GAB1, SOS1, MAPK1, RAB11A, CAV1, and RANBP9), and tumor suppression (CCDC6). Moreover, ectopic BART miRNA expression in several EBV-negative BL cells induced transcriptional changes that may influence molecular signatures of EBV-associated BLs. Collectively, our findings reveal novel, functional interactions for BART miRNAs in lymphomas and provide insights into their roles in these B cell cancers. Full article

Exercise is increasingly recognized as an effective strategy to counteract skeletal muscle aging and conditions such as sarcopenia. However, the specific exercise-induced genes responsible for these protective effects remain unclear. To address this, we conducted an eight-week aerobic exercise regimen on late-middle-aged mice and developed an integrated approach that combines mouse exercise-induced genes with human GWAS datasets to identify causal genes for sarcopenia. This approach led to significant improvements in the skeletal muscle phenotype of the mice and the identification of exercise-induced genes and miRNAs. By constructing a miRNA regulatory network enriched with transcription factors and GWAS signals related to muscle function and traits, we focused on 896 exercise-induced genes. Using human skeletal muscle cis-eQTLs as instrumental variables, 250 of these exercise-induced genes underwent two-sample Mendelian randomization analysis, identifying 40, 68, and 62 causal genes associated with sarcopenia and its clinical indicators—appendicular lean mass (ALM) and hand grip strength (HGS), respectively. Sensitivity analyses and cross-phenotype validation confirmed the robustness of our findings. Consistently across the three outcomes, RXRA, MDM1, RBL2, KCNJ2, and ADHFE1 were identified as risk factors, while NMB, TECPR2, MGAT3, ECHDC2, and GINM1 were identified as protective factors, all with potential as biomarkers for sarcopenia progression. Biological activity and disease association analyses suggested that exercise exerts its anti-sarcopenia effects primarily through the regulation of fatty acid oxidation. Based on available drug–gene interaction data, 21 of the causal genes are druggable, offering potential therapeutic targets. Our findings highlight key genes and molecular pathways potentially responsible for the anti-sarcopenia benefits of exercise, offering insights into future therapeutic strategies that could mimic the safe and mild protective effects of exercise on age-related skeletal muscle degeneration. Full article

In most human tumors, the MAPK pathway is constitutively activated. Since p90RSK is downstream of MAPK, it is often hyperactive and capable of phosphorylating oncogenic substrates. We have previously shown that p90RSK phosphorylates MDM2 at S166, promoting p53 degradation in follicular thyroid carcinomas. Thus, the inhibition of p90RSK restores p53 expression, which in turn inhibits cell proliferation and promotes apoptosis. In the present study, we demonstrated that the p90RSK/MDM2/p53 pathway proved to be an excellent target in the therapy of tumors with MAPK hyperactivation. For this purpose, we selected p53wt melanoma, lung and medullary thyroid carcinoma cell lines with high activation of p90RSK. In these cell lines, we demonstrated that the p90RSK/MDM2/p53 pathway is implicated in the regulation of the cell cycle and apoptosis through p53-dependent transcriptional control of p21 and Bcl-2. Furthermore, with an immunohistochemical evaluation of primary melanomas and lung tumors, which exhibit highly activated p90RSK compared to corresponding normal tissue, we demonstrated that MDM2 stabilization was associated with p90RSK phosphorylation. The results indicate that p90RSK is able to control the proliferative rate and induction of apoptosis through the regulation of p53wt levels by stabilizing MDM2 in selected tumors with constitutively activated MAPKs, making p90RSK a new attractive target for anticancer therapy. Full article

Excessive fluoride ingestion during tooth development can cause dental fluorosis. Previously, we reported that fluoride activates histone acetyltransferase (HAT) to acetylate p53, promoting fluoride toxicity in mouse ameloblast-like LS8 cells. However, the roles of HAT and histone acetylation status in fluoride-mediated gene expression remain unidentified. Here, we demonstrate that fluoride-mediated histone modification causes gene expression alterations in LS8 cells. LS8 cells were treated with or without fluoride followed by ChIP-Seq analysis of H3K27ac. Genes were identified by differential H3K27ac peaks within ±1 kb from transcription start sites. The levels of mRNA of identified genes were assessed using rea-time PCR (qPCR). Fluoride increased H3K27ac peaks associated with Bax, p21, and Mdm2 genes and upregulated their mRNA levels. Fluoride decreased H3K27ac peaks and p53, Bad, and Bcl2 had suppressed transcription. HAT inhibitors (Anacardic acid or MG149) suppressed fluoride-induced mRNA of p21 and Mdm2, while fluoride and the histone deacetylase (HDAC) inhibitor sodium butyrate increased Bad and Bcl2 expression above that of fluoride treatment alone. To our knowledge, this is the first study that demonstrates epigenetic regulation via fluoride treatment via H3 acetylation. Further investigation is required to elucidate epigenetic mechanisms of fluoride toxicity in enamel development. Full article

The mitochondrial distribution and morphology family 33 gene (MDM33) regulates mitochondrial homeostasis by mediating the mitochondrial fission process in yeast. The wheat head blight Fusarium graminearum contains an FgMdm33 protein that is orthologous to Saccharomyces cerevisiae Mdm33, albeit its function remains unknown. We have reported here the roles of FgMdm33 in regulating fungal morphogenesis, mitochondrial morphology, autophagy, apoptosis, and fungal pathogenicity. The ΔFgmdm33 mutants generated through a homologous recombination strategy in this study exhibited defects in terms of mycelial growth, conidia production, and virulence. Hyphal cells lacking FgMDM33 displayed elongated mitochondria and a dispensable respiratory-deficient growth phenotype, indicating the possible involvement of FgMDM33 in mitochondrial fission. The ΔFgmdm33 mutants displayed a remarkable reduction in the proteolysis of GFP-FgAtg8, whereas the formation of autophagic bodies in the hyphal cells of mutants was recorded under the induction of mitophagy. In addition, the transcriptional expression of the apoptosis-inducing factor 1 gene (FgAIF1) was significantly upregulated in the ΔFgmdm33 mutants. Cumulatively, these results indicate that FgMDM33 is involved in mitochondrial fission, non-selective macroautophagy, and apoptosis and that it regulates fungal growth, conidiation, and pathogenicity of the head blight pathogen. Full article

Carotenoids are naturally occurring tetraterpenoids that play a key role in fruit coloration, and yellow peaches are one of the best sources of carotenoid intake. MYB transcription factors are one of the largest families in plants and play an important role in the regulation of plant secondary metabolite biosynthesis. However, peach MYB family genes have not been fully analyzed, and in particular, MYBs that regulate carotenoid biosynthesis have not been fully characterized. In this study, 190 peach MYB genes, containing 68 1R-MYBs, 118 2R-MYBs, 3 3R-MYBs, and 1 4R-MYB, were identified at the genome level using bioinformatics methods. These 190 MYBs were classified into 27 subfamilies based on their phylogenetic relationships with Arabidopsis thaliana MYB family members, and they were unevenly distributed across eight chromosomes. MYB genes of the same subfamily exhibit similar but not identical gene structures and conserved motifs. The promoter regions contain cis-acting elements associated with stress response, hormone response, and plant growth and development. There were 54 collinear pairs of MYB genes in the peach genome, compared with 233 and 221 collinear pairs with Rosa chinensis and Arabidopsis, respectively. Thirteen differentially expressed genes in the carotenoid biosynthesis pathway in yellow peach were identified by transcriptome sequencing and contained MYB binding sites on their promoters. Based on a phylogenetic analysis, we identified 13 PpMYBs that may be involved in carotenoid biosynthesis, and a correlation analysis revealed that they regulate carotenoid accumulation by positively or negatively regulating the expression of carotenoid biosynthetic genes. Further degradome sequencing screened that mdm-miR858 was able to target PpMYB17 and PpMYB126 involved in the regulation of carotenoid biosynthesis. Our findings provide new insights into the potential role of MYB transcription factors in carotenoid biosynthesis and provide a theoretical basis for their molecular mechanisms. Full article

Background: The Tripartite motif (TRIM) family includes more than 80 distinct human genes. Their function has been implicated in regulating important cellular processes, including intracellular signaling, transcription, autophagy, and innate immunity. During viral infections, macrophages are key components of innate immunity that produce interferons (IFNs) and IL27. We recently published that IL27 and IFNs induce transcriptional changes in various genes, including those involved in JAK-STAT signaling. Furthermore, IL27 and IFNs share proinflammatory and antiviral pathways in monocyte-derived macrophages (MDMs), resulting in both common and unique expression of inflammatory factors and IFN-stimulated genes (ISGs) encoding antiviral proteins. Interestingly, many TRIM proteins have been recognized as ISGs in recent years. Although it is already very well described that TRIM expression is induced by IFNs, it is not fully understood whether TRIM genes are induced in macrophages by IL27. Therefore, in this study, we examined the effect of stimulation with IL27 and type I, II, and III IFNs on the mRNA expression profiles of TRIM genes in MDMs. Methods: We used bulk RNA-seq to examine the TRIM expression profile of MDMs treated with IFNs or IL27. Initially, we characterized the expression patterns of different TRIM subfamilies using a heatmap. Subsequently, a volcano plot was employed to identify commonly differentially expressed TRIM genes. Additionally, we conducted gene ontology analysis with ClueGO to explore the biological processes of the regulated TRIMs, created a gene-gene interaction network using GeneMANIA, and examined protein-protein interactions with the STRING database. Finally, RNA-seq data was validated using RT-qPCR. Furthermore, the effect of IL27 on Mayaro virus replication was also evaluated. Results: We found that IL27, similar to IFNs, upregulates several TRIM genes’ expression in human macrophages. Specifically, we identified three common TRIM genes (TRIM19, 21, and 22) induced by IL27 and all types of human IFNs. Additionally, we performed the first report of transcriptional regulation of TRIM19, 21, 22, and 69 genes in response to IL27. The TRIMs involved a broad range of biological processes, including defense response to viruses, viral life cycle regulation, and negative regulation of viral processes. In addition, we observed a decrease in Mayaro virus replication in MDMs previously treated with IL27. Conclusions: Our results show that IL27, like IFNs, modulates the transcriptional expression of different TRIM-family members involved in the induction of innate immunity and an antiviral response. In addition, the functional analysis demonstrated that, like IFN, IL27 reduced Mayaro virus replication in MDMs. This implies that IL27 and IFNs share many similarities at a functional level. Moreover, identifying distinct TRIM groups and their differential expressions in response to IL27 provides new insights into the regulatory mechanisms underlying the antiviral response in human macrophages. Full article

P53 overexpression plays a critical role in cancer pathogenesis by disrupting the intricate regulation of cellular proliferation. Despite its firmly established function as a tumor suppressor, elevated p53 levels can paradoxically contribute to tumorigenesis, influenced by factors such as exposure to carcinogens, genetic mutations, and viral infections. This phenomenon is observed across a spectrum of cancer types, including bladder (BLCA), ovarian (OV), cervical (CESC), cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), diffuse large B-cell lymphoma (DLBC), esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and uterine corpus endometrial carcinoma (UCEC). This broad spectrum of cancers is often associated with increased aggressiveness and recurrence risk. Effective therapeutic strategies targeting tumors with p53 overexpression require a comprehensive approach, integrating targeted interventions aimed at the p53 gene with conventional modalities such as chemotherapy, radiation therapy, and targeted drugs. In this extensive study, we present a detailed analysis shedding light on the multifaceted role of TP53 across various cancers, with a specific emphasis on its impact on disease-free survival (DFS). Leveraging data from the TCGA database and the GTEx dataset, along with GEPIA, UALCAN, and STRING, we identify TP53 overexpression as a significant prognostic indicator, notably pronounced in prostate adenocarcinoma (PRAD). Supported by compelling statistical significance (p < 0.05), our analysis reveals the distinct influence of TP53 overexpression on DFS outcomes in PRAD. Additionally, graphical representations of overall survival (OS) underscore the notable disparity in OS duration between tumors exhibiting elevated TP53 expression (depicted by the red line) and those with lower TP53 levels (indicated by the blue line). The hazard ratio (HR) further emphasizes the profound impact of TP53 on overall survival. Moreover, our investigation delves into the intricate TP53 protein network, unveiling genes exhibiting robust positive correlations with TP53 expression across 13 out of 27 cancers. Remarkably, negative correlations emerge with pivotal tumor suppressor genes. This network analysis elucidates critical proteins, including SIRT1, CBP, p300, ATM, DAXX, HSP 90-alpha, Mdm2, RPA70, 14-3-3 protein sigma, p53, and ASPP2, pivotal in regulating cell cycle dynamics, DNA damage response, and transcriptional regulation. Our study underscores the paramount importance of deciphering TP53 dynamics in cancer, providing invaluable insights into tumor behavior, disease-free survival, and potential therapeutic avenues. Full article

The AP-1 protein complex primarily consists of several proteins from the c-Fos, c-Jun, activating transcription factor (ATF), and Jun dimerization protein (JDP) families. JDP2 has been shown to interact with the cAMP response element (CRE) site present in many cis-elements of downstream target genes. JDP2 has also demonstrates important roles in cell-cycle regulation, cancer development and progression, inhibition of adipocyte differentiation, and the regulation of antibacterial immunity and bone homeostasis. JDP2 and ATF3 exhibit significant similarity in their C-terminal domains, sharing 60–65% identities. Previous studies have demonstrated that ATF3 is able to influence both the transcriptional activity and p53 stability via a p53-ATF3 interaction. While some studies have shown that JDP2 suppresses p53 transcriptional activity and in turn, p53 represses JDP2 promoter activity, the direct interaction between JDP2 and p53 and the regulatory role of JDP2 in p53 transactivation have not been explored. In the current study, we provide evidence, for the first time, that JDP2 interacts with p53 and regulates p53 transactivation. First, we demonstrated that JDP2 binds to p53 and the C-terminal domain of JDP2 is crucial for the interaction. Second, in p53-null H1299 cells, JDP2 shows a robust increase of p53 transactivation in the presence of p53 using p53 (14X)RE-Luc. Furthermore, JDP2 and ATF3 together additively enhance p53 transactivation in the presence of p53. While JDP2 can increase p53 transactivation in the presence of WT p53, JDP2 fails to enhance transactivation of hotspot mutant p53. Moreover, in CHX chase experiments, we showed that JDP2 slightly enhances p53 stability. Finally, our findings indicate that JDP2 has the ability to reverse MDM2-induced p53 repression, likely due to decreased levels of MDM2 by JDP2. In summary, our results provide evidence that JDP2 directly interacts with p53 and decreases MDM2 levels to enhance p53 transactivation, suggesting that JDP2 is a novel regulator of p53 and MDM2. Full article

The transcription factor E2F links the RB pathway to the p53 pathway upon loss of function of pRB, thereby playing a pivotal role in the suppression of tumorigenesis. E2F fulfills a major role in cell proliferation by controlling a variety of growth-associated genes. The activity of E2F is controlled by the tumor suppressor pRB, which binds to E2F and actively suppresses target gene expression, thereby restraining cell proliferation. Signaling pathways originating from growth stimulative and growth suppressive signals converge on pRB (the RB pathway) to regulate E2F activity. In most cancers, the function of pRB is compromised by oncogenic mutations, and E2F activity is enhanced, thereby facilitating cell proliferation to promote tumorigenesis. Upon such events, E2F activates the Arf tumor suppressor gene, leading to activation of the tumor suppressor p53 to protect cells from tumorigenesis. ARF inactivates MDM2, which facilitates degradation of p53 through proteasome by ubiquitination (the p53 pathway). P53 suppresses tumorigenesis by inducing cellular senescence or apoptosis. Hence, in almost all cancers, the p53 pathway is also disabled. Here we will introduce the canonical functions of the RB-E2F-p53 pathway first and then the non-classical functions of each component, which may be relevant to cancer biology. Full article