The role of the p53 protein in the apoptotic response

1995 ◽  
pp. 41-44
Author(s):  
D. P. Lane ◽  
Xin Lu ◽  
Ted Hupp ◽  
P. A. Hall
Keyword(s):  
P53 Protein ◽  
Apoptotic Response

Coupling between gamma irradiation, p53 induction and the apoptotic response depends upon cell type in vivo

1995 ◽  
Vol 108 (5) ◽  
pp. 1843-1848 ◽  
Author(s):  
C.A. Midgley ◽  
B. Owens ◽  
C.V. Briscoe ◽  
D.B. Thomas ◽  
D.P. Lane ◽  
...  
Keyword(s):  
P53 Protein ◽  
Whole Body ◽  
Protein Accumulation ◽  
Cell Type ◽  
Apoptotic Response ◽  
Adult Mice ◽  
Specific Manner ◽  
Massive Apoptosis

The accumulation of p53 protein following whole body irradiation of adult mice was studied using a new polyclonal antibody to mouse p53. While dramatic accumulation of the protein was apparent in splenocytes, thymocytes and osteocytes no p53 protein accumulation was detected in the hepatocytes of the irradiated mouse. Thus, the upstream initiating signals that control the induction of p53 are controlled in a tissue specific manner. While massive apoptosis accompanies p53 induction in thymocytes and splenocytes it is not seen in the osteocytes. Thus the downstream consequences of p53 induction are also tightly controlled. These results have profound significance for an understanding of the role of the p53 tumour suppression pathway in different tissues.

scholarly journals Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3465
Author(s):  
Aya Saleh ◽  
Ruth Perets
Keyword(s):  
Cancer Progression ◽  
Target Genes ◽  
P53 Protein ◽  
Genetic Alterations ◽  
Common Mutation ◽  
Missense Mutations ◽  
P53 Expression ◽  
Histologic Subtype ◽  
Tp53 Mutations

Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.

scholarly journals MYC-targeted WDR4 promotes proliferation, metastasis, and sorafenib resistance by inducing CCNB1 translation in hepatocellular carcinoma

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Peng Xia ◽  
Hao Zhang ◽  
Kequan Xu ◽  
Xiang Jiang ◽  
Meng Gao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
P53 Protein ◽  
Rna Modifications ◽  
M Cell ◽  
Mesenchymal Transition ◽  
Akt Phosphorylation ◽  
Repeat Domain ◽  
Cell Cycle Transition

AbstractHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there still remains a lack of effective diagnostic and therapeutic targets for this disease. Increasing evidence demonstrates that RNA modifications play an important role in the progression of HCC, but the role of the N7-methylguanosine (m7G) methylation modification in HCC has not been properly evaluated. Thus, the goal of the present study was to investigate the function and mechanism of the m7G methyltransferase WD repeat domain 4 (WDR4) in HCC as well as its clinical relevance and potential value. We first verified the high expression of WDR4 in HCC and observed that upregulated WDR4 expression increased the m7G methylation level in HCC. WDR4 promoted HCC cell proliferation by inducing the G2/M cell cycle transition and inhibiting apoptosis in addition to enhancing metastasis and sorafenib resistance through epithelial-mesenchymal transition (EMT). Furthermore, we observed that c-MYC (MYC) can activate WDR4 transcription and that WDR4 promotes CCNB1 mRNA stability and translation to enhance HCC progression. Mechanistically, we determined that WDR4 enhances CCNB1 translation by promoting the binding of EIF2A to CCNB1 mRNA. Furthermore, CCNB1 was observed to promote PI3K and AKT phosphorylation in HCC and reduce P53 protein expression by promoting P53 ubiquitination. In summary, we elucidated the MYC/WDR4/CCNB1 signalling pathway and its impact on PI3K/AKT and P53. Furthermore, the result showed that the m7G methyltransferase WDR4 is a tumour promoter in the development and progression of HCC and may act as a candidate therapeutic target in HCC treatment.

scholarly journals Adaptive response of the skin to UVB damage: role of the p53 protein

2006 ◽  
Vol 28 (1) ◽  
pp. 1-7 ◽  
Author(s):  
L. Verschooten ◽  
L. Declercq ◽  
M. Garmyn
Keyword(s):  
Adaptive Response ◽  
P53 Protein

Role of P53 Mutations in the Radiosensitivity Status of Tumor Cells

1998 ◽  
Vol 84 (5) ◽  
pp. 517-520 ◽  
Author(s):  
Vincenzo Chiarugi ◽  
Lucia Magnelli ◽  
Marina Cinelli
Keyword(s):  
Dna Damage ◽  
Cellular Response ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
P53 Mutations ◽  
Wild Type ◽  
Bladder Tumors ◽  
Variable Effect ◽  
Wild Type P53

Wild-type p53 is involved in cellular response to DNA damage including cell cycle control, DNA repair and activation of apoptosis. Accumulation of p53 protein following DNA damage may initiate the apoptotic process, resulting in cell death. DNA damage induced by radiation is an example of apoptotic stimulus involving p53. Regulation of apoptosis by p53 can occur through transcriptional regulation of pro-apoptotic (e.g. bax) and anti-apoptotic (e.g. bel-2) factors. Although wild-type p53 usually sensitizes cells to radiation therapy, p53 mutations have a variable effect on radiation response. For example p53 mutations in bone or breast tumors have been found to be associated with resistance to chemotherapeutic drugs or ionizing radiation. Mutated p53 has has been reported to increase sensitivity to radiation and drugs in colorectal and bladder tumors. The present brief commentary tries to find an explanation at molecular level of these conflicting results.

scholarly journals p21WAF1 expression by an activator of protein kinase C is regulated mainly at the post-transcriptional level in cells lacking p53: important role of RNA stabilization

1999 ◽  
Vol 337 (3) ◽  
pp. 607-616 ◽  
Author(s):  
Makoto AKASHI ◽  
Yoshiaki OSAWA ◽  
H. Phillip KOEFFLER ◽  
Misao HACHIYA
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phorbol Esters ◽  
P53 Protein ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Transcriptional Level ◽  
Kinase C ◽  
In Cells

p21WAF1 inhibits cyclin–cyclin-dependent kinase (Cdk) complexes, causing cell cycle arrest. p21WAF1 contains p53-binding sites in its promoter and expression of p21WAF1 is induced by functional p53. In the present work, we have studied the role of protein kinase C (PKC) in the induction of p21WAF1 and show that induction of p21WAF1 expression can occur by activation of PKC in cells having no p53. Human ovarian carcinoma cells, SKOV-3, lack p53 protein and PMA, a potent activator of PKC, did not induce p53. PMA increased the expression of p21WAF1 mRNA both in these cells and in other cells which do not contain p53 (THP-1 and U937). Treatment of human embryonic fibroblasts, WI38, with PMA also induced the accumulation of p21WAF1 without affecting p53 levels. However, PMA did not increase levels of p21WAF1 mRNA in cells where either the PKC or the mitogen-activated protein kinase pathway was blocked. Furthermore, treatment of cells with various phorbol ester derivatives which activate PKC resulted in the induction of p21WAF1 in SKOV-3 cells. In contrast, phorbol esters which do not activate PKC failed to induce p21WAF1 expression. PMA increased the transcriptional rate of p21WAF1 and activated the transcription of a luciferase reporter gene, controlled by the p21 promoter, in SKOV-3 cells with or without a p53 consensus-binding sequence. By contrast, PMA markedly stabilized p21WAF1 mRNA; the half-life (t1/2) of p21WAF1 in PMA-treated cells was > 8 h compared with < 1 h in untreated cells. These findings provide evidence that the PKC pathway induces expression of p21WAF1 independently of p53. Our present study also suggests that the accumulation of p21WAF1 transcripts by PMA occurs mainly at post-transcriptional level.

scholarly journals Localization of Tricellular Tight Junction Molecule LSR at Midbody and Centrosome During Cytokinesis in Human Epithelial Cells

2019 ◽  
Vol 68 (1) ◽  
pp. 59-72 ◽  
Author(s):  
Takumi Konno ◽  
Takayuki Kohno ◽  
Shin Kikuchi ◽  
Hiroshi Shimada ◽  
Seiro Satohisa ◽  
...  
Keyword(s):  
Tight Junction ◽  
Barrier Function ◽  
P53 Protein ◽  
Epithelial Barrier ◽  
Small Interfering Rnas ◽  
Acetylated Tubulin ◽  
Zonula Occludens ◽  
Junction Molecules ◽  
Endometrial Carcinoma Cell Line

Epithelial integrity and barrier function are maintained during cytokinesis in vertebrate epithelial tissues. The changes in localization and the roles of tricellular tight junction molecule lipolysis-stimulated lipoprotein receptor (LSR) during cytokinesis are not well known, although new tricellular tight junctions form at the flank of the midbody during cytokinesis. In this study, we investigated the changes in localization and the role of LSR at the midbody and centrosome during cytokinesis using human endometrial carcinoma cell line Sawano, comparing the tricellular tight junction molecule tricellulin; bicellular tight junction molecules occludin, claudin-7, zonula occludens-1, and cingulin; and the epithelial polarized related molecules apoptosis-stimulating of p53 protein 2, PAR3, and yes-associated protein. During cytokinesis induced by treatment with taxol, the epithelial barrier was maintained and the tricellular tight junction molecules LSR and tricellulin were concentrated at the flank of the acetylated tubulin–positive midbody and in γ-tubulin-positive centrosomes with the dynein adaptor Hook2, whereas the other molecules were localized there as well. All the molecules disappeared by knockdown using small interfering RNAs. Furthermore, by the knockdown of Hook2, the epithelial barrier was maintained and most of the molecules disappeared from the centrosome. These findings suggest that LSR may play crucial roles not only in barrier function but also in cytokinesis.

Antitumor Genotoxic Agents, Such as Fludarabine*, Doxorubincin or Cis-Platine, Induce Activation of STAT1 in a p53 Protein Dependent Manner.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4384-4384
Author(s):  
Ibtissam Youlyouz-Marfak ◽  
Christophe Le Clorennec ◽  
Imen Najjar ◽  
Fanny Baran-Marszak ◽  
Nathalie Gachard ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
P53 Protein ◽  
Surrogate Marker ◽  
Dependent Manner ◽  
Hl60 Cells ◽  
Over Expression ◽  
Cellular Models ◽  
Genotoxic Agents ◽  
P53 Activation

Abstract Introduction: Chemotherapeutic drug such as Fludarabine*; doxorubicin or cis-platine induce cell cycle arrest and apoptosis via activation of p53. Convergent studies suggest that p53 and STAT1 cooperate in the induction of apoptosis, and that STAT1 favors p53 activation. However, to our knowledge, the role of p53 in the activation of STAT1 is not documented. We present our results suggesting that (i) genotoxic agents are STAT1 inducers, (ii) STAT1 activation depends on the presence of p53 protein, and (iii) this phenomenon is modulated by the tyrosine kinase inhibitor STI571. Materials and Methods: To analyse the role of p53 in STAT1 activation, we have used different cellular models with different p53 status: PRI (p53wt), BL2 (p53wt), BL41 (p53 mutated on Arg248, resulting in the loss of p53 DNA binding activity (p53mut)), Jurkat, HL60 and MEF (the 3 latter being p53 null). The following cDNAs were used for functional studies: p53wt, p53mut, MDM2 and MTBP (MDM2 transforming protein). These cDNAs were cloned either in a pcDNA3 vector or a pRT-1 inducible vector (in the latter, the gene of interest is expressed from a bidirectional doxycycline regulatable promoter allowing simultaneous expression of truncated NGF receptor, used as a surrogate marker of inducibility). Results: Treatment of the different cell lines with the 3 genotoxic drugs Fludarabine*, doxorubicin or cis-platine induced STAT1 activation in p53wt BL2 or PRI cells and in p53mut BL41 cells, but not in Jurkat cells neither in HL60 or MEF cells. Induction of STAT1 was also obtained in presence of the RNA synthesis inhibitor Actinomycin D or in presence of secretion inhibitor Brefeldine A. Over-expression of p53wt or p53mut markedly increased STAT1 activation in PRI cells. This effect was reversed by over-expression of MTBP. Complementation of both HL60 and MEF cells with both p53wt and p53mut cDNA induced constitutive STAT1 activation, an effect that was increased by treatment with doxorubine in transfected HL60 cells. This effect was reversed by over-expression of MDM2 in HL60 cells. Finally, we found that treatment of cells with the inhibitor STI 571 of c-Abl tyrosine kinase, a kinase known to be associated with ATM during p53 activation, decreased STAT1 activation by genotoxic drugs. Conclusion: Our results show that genotoxic agents are inducers of STAT1, that p53 protein but not p53 transcriptional activity is responsible for this STAT1 activation, and suggest a possible involvement the cABL tyrosine kinase.

scholarly journals The transcription factor early growth response factor-1 (EGR-1) promotes apoptosis of neuroblastoma cells

2003 ◽  
Vol 373 (3) ◽  
pp. 739-746 ◽  
Author(s):  
Miguel PIGNATELLI ◽  
Rosario LUNA-MEDINA ◽  
Arturo PÉREZ-RENDÓN ◽  
Angel SANTOS ◽  
Ana PEREZ-CASTILLO
Keyword(s):  
Growth Response ◽  
P53 Protein ◽  
Early Growth ◽  
Early Gene ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Response Factor ◽  
P53 Family ◽  
Early Growth Response ◽  
In Cells

Early growth response factor-1 (EGR-1) is an immediate early gene, which is rapidly activated in quiescent cells by mitogens or in postmitotic neurons after depolarization. EGR-1 has been involved in diverse biological functions such as cell growth, differentiation and apoptosis. Here we report that enforced expression of the EGR-1 gene induces apoptosis, as determined by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick-end labelling (TUNEL) analysis, in murine Neuro2A cells. In accordance with this role of EGR-1 in cell death, antisense oligonucleotides increase cell viability in cells cultured in the absence of serum. This apoptotic activity of the EGR-1 appears to be mediated by p73, a member of the p53 family of proteins, since an increase in the amount of p73 is observed in clones stably expressing the EGR-1 protein. We also observed an increase in the transcriptional activity of the mdm2 promoter in cells overexpressing EGR-1, which is paralleled by a marked decrease in the levels of p53 protein, therefore excluding a role of this protein in mediating EGR-1-induced apoptosis. Our results suggest that EGR-1 is an important factor involved in neuronal apoptosis.

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