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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genomic instability is a hallmark of cancer development and progression, and characterizing the stresses that create and the mechanisms by which cells respond to genomic perturbations is essential. Here we demonstrate that antiapoptotic BCL-2 family proteins promoted tumor formation of transformed baby mouse kidney (BMK) epithelial cells by antagonizing BAX- and BAK-dependent apoptosis. Cell death in vivo correlated with hypoxia and induction of PUMA (p53 up-regulated modulator of apoptosis). Strikingly, carcinomas formed by transformed BMK cells in which apoptosis was blocked by aberrant BCL-2 family protein function displayed prevalent, highly polyploid, tumor giant cells. Examination of the transformed BMK cells in vivo revealed aberrant metaphases and ploidy changes in tumors as early as 9 d after implantation, which progressed in magnitude during the tumorigenic process. An in vitro ischemia system mimicked the tumor microenvironment, and gain of BCL-2 or loss of BAX and BAK was sufficient to confer resistance to apoptosis and to allow for accumulation of polyploid cells in vitro. These data suggest that in vivo, even in cells in which p53 function is compromised, apoptosis is an essential response to hypoxia and ischemia in the tumor microenvironment and that abrogation of this response allows the survival of cells with abnormal genomes and promotes tumorigenesis.
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PMID:Hypoxia and defective apoptosis drive genomic instability and tumorigenesis. 1531 31

In the present work, we show that mithramycin A, a drug that is currently used for the treatment of patients with Paget's disease of the bone as well as with several forms of cancer, is a strong activator of the tumor suppressor p53 protein in human hepatoma cells. The time course of p53 activation by mithramycin A was similar to the known chemotherapeutic compound 5-fluorouracil (5-FU). Both 5-FU and mithramycin A induced site-specific phosphorylation of p53 at serine 15. However, in contrast to 5-FU, mithramycin A failed to activate p53 target genes including the cell cycle inhibitor p21Cip1 gene as well as the proapoptotic genes PUMA (p53-upregulated mediator of apotosis) and BAK (bcl2-homologous antagonist/killer) and blocked the induction of the above genes by 5-FU. Using transactivation assays in Sp1-deficient cells, we showed that mithramycin A inhibited the transcriptional activation of the p21Cip1 and PUMA promoters by Sp1 and p53. Using chromatin immunoprecipitation assays and a novel protein-protein interaction assay based on biotinylation in vivo, we established that 5-FU enhanced the formation of p53-Sp1 complexes in solution and the subsequent recruitment of both factors to the p21Cip1 promoter. Mithramycin A also enhanced the recruitment of p53 to the distal p21Cip1 promoter but totally blocked the recruitment of Sp1 to the proximal p21Cip1 promoter. Our findings suggest that inhibition of Sp1 binding to the promoters of several p53 target genes, such as the p21Cip1 gene as well as certain proapoptotic genes, by mithramycin A, prevents the transcriptional induction of these genes by p53 and propose a mechanism that could account for some of the tumor suppressing and antiapoptotic effects of mithramycin A.
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PMID:Inhibition of p53-mediated transcriptional responses by mithramycin A. 1548 92

The p53 tumor suppressor gene has been implicated in the regulation of apoptosis in a number of different neuronal death paradigms. Because of the importance of p53 in neuronal injury, we questioned the mechanism underlying p53-mediated apoptosis in neurons. Using adenoviral-mediated gene delivery, reconstitution experiments, and mice carrying a knock-in mutation in the endogenous p53 gene, we show that the transactivation function of p53 is essential to induce neuronal cell death. Although p53 possesses two transactivation domains that can activate p53 targets independently, we demonstrate that the first activation domain (ADI) is required to drive apoptosis after neuronal injury. Furthermore, the BH3-only proteins Noxa and PUMA exhibit differential regulation by the two transactivation domains. Here, we show that Noxa can be induced by either activation domain, whereas PUMA induction requires both activation domains to be intact. Unlike Noxa, the upregulation of PUMA alone is sufficient to induce neuronal cell death. We demonstrate, therefore, that the first transactivation domain of p53 is indispensable for the induction of neuronal cell death.
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PMID:p53 activation domain 1 is essential for PUMA upregulation and p53-mediated neuronal cell death. 1552 86

PUMA is a BH3-only member of the Bcl-2 family, up-regulated by p53 as a response to DNA damage. We have investigated the mRNA expression of PUMA with real-time PCR in 94 colorectal adenocarcinomas and the corresponding normal mucosa. Among them PUMA protein expression was investigated with immunohistochemistry in 23 tumours and 17 corresponding normal mucosa samples. The mRNA expression of PUMA decreased in 4% and increased in 4% of the tumours compared with the normal mucosa. The protein expression of PUMA decreased in 6% and increased in 29% of the tumours compared with the normal mucosa. Decreased PUMA expression in the tumour compared with the corresponding mucosa was correlated with the distal colon and rectum (P=0.02). We did not find any other relationship to clinical or pathological features. We suggest that the changes in PUMA expression may be of minor importance in the development of colorectal cancer.
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PMID:mRNA and protein expression of PUMA in sporadic colorectal cancer. 1554 45

The majority of colorectal cancers have lost/inactivated the p53 tumor suppressor gene. Using isogenic human colon cancer cells that differ only in their p53 status, we demonstrate that loss of p53 renders tumor cells relatively resistant to the topoisomerase I inhibitor, irinotecan. Whereas irinotecan-induced up-regulation of the proapoptotic proteins PUMA and Noxa requires p53, we find that irinotecan inhibits Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 and 5 (STAT3/5) signaling in both p53-proficient and p53-deficient tumor cells. We show that irinotecan inhibits JAK2-STAT3/5-dependent expression of survival proteins (Bcl-x(L) and XIAP) and cooperates with Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) to facilitate p53-independent apoptosis of colon cancer cells. Whereas xenografts of p53-deficient colon cancer cells are relatively resistant to irinotecan compared with their p53-proficient counterparts, combined treatment with irinotecan and Apo2L/TRAIL eliminates hepatic metastases of both p53-proficient and p53-deficient cancer cells in vivo and significantly improves the survival of animals relative to treatment with either agent alone. Although the synergy between chemotherapy and Apo2L/TRAIL has been ascribed to p53, our data demonstrate that irinotecan enhances Apo2L/TRAIL-induced apoptosis of tumor cells via a distinct p53-independent mechanism involving inhibition of JAK2-STAT3/5 signaling. These findings identify a novel p53-independent channel of cross-talk between topoisomerase I inhibitors and Apo2L/TRAIL and suggest that the addition of Apo2L/TRAIL can improve the therapeutic index of irinotecan against both p53-proficient and p53-deficient colorectal cancers, including those that have metastasized to the liver.
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PMID:Elimination of hepatic metastases of colon cancer cells via p53-independent cross-talk between irinotecan and Apo2 ligand/TRAIL. 1560 80

The p53 tumor suppressor promotes apoptosis in response to DNA damage. Here we describe the Caenorhabditis elegans gene ced-13, which encodes a conserved BH3-only protein. We show that ced-13 mRNA accumulates following DNA damage, and that this accumulation is dependent on an intact C. elegans cep-1/p53 gene. We demonstrate that CED-13 protein physically interacts with the antiapoptotic Bcl-2-related protein CED-9. Furthermore, overexpression of ced-13 in somatic cells leads to the death of cells that normally survive, and this death requires the core apoptotic pathway of C. elegans. Recent studies have implicated two BH3-only proteins, Noxa and PUMA, in p53-induced apoptosis in mammals. Our studies suggest that in addition to the BH3-only protein EGL-1, CED-13 might also promote apoptosis in the C. elegans germ line in response to p53 activation. We propose that an evolutionarily conserved pathway exists in which p53 promotes cell death by inducing expression of two BH3-only genes.
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PMID:C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage. 1560 74

TP73, as a TP53 homologue, drew the attention of tumor biologists because it is rarely mutated in human cancers and can induce cell cycle arrest and apoptosis by activating genes also regulated by p53. However, TP73 harbors an additional promoter that produces a dominant negative p73 protein (deltaNp73) having the opposite effect of the TAp73 protein. Thus, the regulation of p53 responsive genes in the absence of p53 relies on a critical balance between different p73 gene-derived proteins. Recent reports have described additional complexity in the mechanism of action of transcriptionally active p73 (TAp73) in the induction of cell death. The molecular mechanism through which p73 induces apoptosis involves (i) expression and changes in subcellular localization of scotin, producing an endoplasmic reticulum (ER) stress; and (ii) transactivation of PUMA and Bax, thus determining cell fate. On the contrary, deltaNp73 inhibits apoptosis, thus contributing to the oncogenic potential of neuroblastoma cells.
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PMID:Mechanism of induction of apoptosis by p73 and its relevance to neuroblastoma biology. 1565 Feb 40

Cutaneous malignant melanoma is an aggressive form of skin cancer, characterized by strong chemoresistance and poor patient prognosis. The molecular mechanisms underlying its resistance to chemotherapy remain unclear but are speculated to involve the dysregulation of apoptotic pathways. In this study, we sought to determine whether PUMA (p53 upregulated modulator of apoptosis) contributes to human melanoma formation, tumor progression, and survival. We used tissue microarray and immunohistochemistry to examine PUMA expression in 107 primary melanomas, 51 metastatic melanomas, and 64 dysplastic nevi. Here we report that PUMA expression is significantly weaker in primary melanomas compared to dysplastic nevi (P<0.0001), and is further reduced in metastatic melanomas compared to primary tumors (P=0.001). We show that weak PUMA expression in melanoma correlates with poorer overall and disease-specific 5-year survival (P<0.005 and P<0.001, respectively) of melanoma patients and that PUMA expression in tumor tissue is an independent predictor of both overall and disease-specific 5-year survival (P=0.05). Additionally, we show that exogenous PUMA expression in human melanoma cell lines (both wild type and mutant p53) results in significant apoptotic cell death. Our results suggest that PUMA expression may be an important prognostic marker for human melanoma and that adenoviral delivery of PUMA sensitizes melanoma cells to apoptosis.
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PMID:PUMA expression is significantly reduced in human cutaneous melanomas. 1569 57

Increased amounts of reactive oxygen species (ROS) induce apoptosis in mammalian cells. PUMA (P53 up-regulated modulator of apoptosis), a mitochondrial proapoptotic BH3-only protein, induces rapid apoptosis through a Bax- and mitochondria-dependent pathway. However, the molecular basis of PUMA-induced apoptosis is largely not understood. Using a combination of biophysical and biochemical methods and PUMA-inducible colorectal cells, DLD-1.PUMA, we showed that (a) PUMA-induced apoptosis is dose and time dependent; (b) PUMA-induced apoptosis is directly associated with ROS generation; (c) diphenyleneiodonium chloride, a ROS blocker, or BAX-inhibiting peptide, a suppressor of BAX translocation, decreased ROS generation and apoptosis in DLD-1.PUMA cells; (d) overexpression of PUMA induced up-regulation (>1.34-fold) of peroxiredoxin 1 and down-regulation (by 25%) of stathmin through proteasome-mediated degradation; and (e) hydrogen peroxide down-regulated stathmin and disrupted the cellular microtubule network. Our findings indicate that PUMA induces apoptosis, in part, through the BAX-dependent generation of superoxide and hydrogen peroxide. ROS overproduction and oxidative stress induce proteome-wise alterations, such as stathmin degradation and disorganization of the cell microtubule network, in apoptotic cells.
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PMID:PUMA overexpression induces reactive oxygen species generation and proteasome-mediated stathmin degradation in colorectal cancer cells. 1575 58

In the present study, we have investigated mechanisms of transcriptional co-operation between proteins that belong to the tumour suppressor p53 and Sp (specificity protein) families of transcription factors. Such mechanisms may play an important role in the regulation of genes containing binding sites for both classes of transcription factors in their promoters. Two of these genes were analysed in the present study: the cyclin-dependent kinase inhibitor p21Cip1 gene and the PUMA (p53-up-regulated mediator of apoptosis) gene. We found that Sp1 and Sp3, but not Sp2, co-operate functionally with p53, p73 and p63 for the synergistic transactivation of the p21Cip1 promoter in Drosophila Schneider SL2 cells that lack endogenous Sp factors. We also found that Sp1 strongly transactivated the PUMA promoter synergistically with p53, whereas deletion of the Sp1-binding sites abolished the transactivation by p53. Using p53 mutant forms in GST (glutathione S-transferase) pull-down assays, we found that the C-terminal 101 amino acids of p53, which include the oligomerization and regulatory domains of the protein, are required for the physical interactions with Sp1 and Sp3, and that deletion of this region abolished transactivation of the p21Cip1 promoter. Utilizing truncated forms of Sp1, we established that p53 interacted with the two transactivation domains A and B, as well as the DNA-binding domain. Our findings suggest that Sp factors are essential for the cellular responses to p53 activation by genotoxic stress. Understanding in detail how members of the p53 and Sp families of transcription factors interact and work together in the p53-mediated cellular responses may open new horizons in cancer chemotherapy.
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PMID:Physical and functional interactions between members of the tumour suppressor p53 and the Sp families of transcription factors: importance for the regulation of genes involved in cell-cycle arrest and apoptosis. 1579 Mar 10


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