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

The transcription regulatory function of p53 was analyzed by using two inducible p53 systems in the human lung cancer cell line H1299. cDNA probes derived from RNA harvested 12 h after p53 induction were used to probe filters containing cDNA arrays. Over 20 genes were found to be significantly induced or suppressed by p53. The induced genes can be classified mainly as cell cycle inhibitors like p21waf, GADD45, apoptosis-related genes like Fas/APO1 and PIG3 or DNA repair genes like DDB2, DNA ligase and G/T mismatch DNA glycosylase. The suppressed genes include mainly cell cycle regulators like cyclin B1, cyclin H and kinases like c-abl, CLK1 and others. The most notable induced gene was MIC-1, encoding a TGF-beta-related secretory protein, suggesting a potential paracrine component for p53 growth suppression.
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PMID:Profile of gene expression regulated by induced p53: connection to the TGF-beta family. 1072 49

The p53 tumour suppressor phosphoprotein associates with proteins involved in DNA replication, transcription, cell cycle machinery and regulation of its own expression. Recently it has been shown that p53 can also bind to trk A tyrosine kinase which is the receptor for nerve growth factor (NGF). This study demonstrates that p53 appears to associate with trk A via c-abl. Endogenous c-abl was detected when the trk A and p53 complex was immunoprecipitated from lysates of NGF stimulated NIH3T3 cells expressing trk A or NIH3T3 cells expressing trk A and a temperature sensitive p53 (val 135). Endogenous c-abl and trk A association was observed in NGF stimulated p53 negative fibroblasts transfected with trk A alone; suggesting that c-abl can independently bind to trk A in the absence of p53. Interestingly, association between endogenous p53 and trk A was not detected in NGF stimulated abl negative fibroblasts transfected with trk A or when these cells were exposed to gamma radiation. This result suggests that p53 preferentially binds to trk A in the presence of c-abl and that p53 and trk A do not appear to associate directly even if p53 is activated and its levels increased by gamma radiation. Overall, these data suggest that c-abl is possibly acting as an adaptor or bridge between p53 and trk A. Oncogene (2000).
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PMID:c-abl is involved in the association of p53 and trk A. 1087 55

The c-abl proto-oncogene encodes a protein tyrosine kinase that is distributed in the nucleus and the cytoplasm of proliferating cells. In the nucleus, c-Abl activity is negatively regulated by the retinoblastoma protein (RB) and positively regulated by DNA damage signals. Activation of the c-Abl kinase by DNA damage requires the function of ATM, which regulates cell cycle checkpoint, DNA repair and apoptosis in response to DNA damage. Cells lacking c-Abl can activate cell cycle checkpoints and DNA repair, but show defects in apoptosis. The apoptosis defect of c-Abl deficient cells is correlated with a defect in the induction and activation of p73, which is a functional homologue of the p53 tumor suppressor protein and has pro-apoptotic activity. The inhibition of c-Abl by RB is consistent with RB's ability to block apoptosis; while the activation of c-Abl by ATM is consistent with ATM's ability to activate cell death. The oncogenic Bcr-Abl tyrosine kinase is a potent inhibitor of apoptosis, and it is retained exclusively in the cytoplasm of transformed cells. Interestingly, when Bcr-Abl is trapped inside of the nucleus through a combined disruption of its cytoplasmic retention and its nuclear export, this oncogenic Abl kinase induces apoptosis. Taken together, the current results support a role for the nuclear c-Abl tyrosine kinase in the regulation of apoptosis. Whether the cytoplasmic c-Abl kinase can actively inhibit apoptosis remains to be determined; however, a deliberate retention of c-Abl in the cytoplasm could potentially contribute to the attenuation of apoptosis response.
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PMID:Regulation of cell death by the Abl tyrosine kinase. 1111 45

ik3-1/Cables is associated with cdk3 in self-replicating cells. In postmitotic neurons, it may serve as an adaptor molecule, functionally connecting c-abl and cdk5, and supporting neurite growth. Here we report that ik3-1 binds to p53 and p73 in vivo. Ectopically expressed ik3-1 potentiates p53-induced cell death but not p73-induced cell death in U2OS cells. On the contrary, coexpression of ik3-1-DeltaC, an ik3-1 deletion mutant lacking the C-terminal 139 [corrected] amino acids (corresponding to the cyclin box-homologous region), inhibits p73-induced cell death but not p53-induced cell death. ik3-1-DeltaC-mediated inhibition of p73-induced cell death are partially attenuated by overexpression of ik3-1. These data indicate that ik3-1 is not only a regulator for p53-induced cell death but also an essential regulator for p73-induced cell death, and ik3-1-DeltaC competes with ik3-1 only in p73-induced cell death. Furthermore, functional domains of p53 responsible for its interaction with ik3-1 are partially different from those of p73. In conclusion, we found that ik3-1, a putative component of cell cycle regulation, is functionally connected with p53 and p73, but in distinct fashions.
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PMID:Differential effect of ik3-1/cables on p53- and p73-induced cell death. 1170 30

The tumor suppressor p53 and its close relative p73 are activated in response to DNA damage resulting in either cell cycle arrest or apoptosis. Here, we show that DNA damage induces the acetylation of p73 by the acetyltransferase p300. Inhibiting the enzymatic activity of p300 hampers apoptosis in a p53(-/-) background. Furthermore, a nonacetylatable p73 is defective in activating transcription of the proapoptotic p53AIP1 gene but retains an intact ability to regulate other targets such as p21. Finally, p300-mediated acetylation of p73 requires the protooncogene c-abl. Our results suggest that DNA damage-induced acetylation potentiates the apoptotic function of p73 by enhancing the ability of p73 to selectively activate the transcription of proapoptotic target genes.
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PMID:DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes. 1180 96

To define genetic aberrations playing a role in the development of enteropathy-type T-cell lymphoma (ETL), we examined 26 such tumors using a battery of 47 microsatellite markers. The most frequent aberration (seen in 40% of informative genotypes) was amplification of genomic material in region 9q34 encompassing c-abl and Notch-1 gene loci. Other frequent amplifications were detected in regions 5q33.3-34 and 7q31 (both in more than 30%). Multiple losses of heterozygosity were detected in 6p24, 7p21, 17q23-25, regions containing putative tumor suppressor genes, and in the p53 locus in 17p13.1. Analysis of the pattern of occurrence of these aberrations revealed existence of two ETL subgroups: one of them characterized by the 9q34 aberration and another smaller one showing allelic imbalances in 3q27. These two aberrations were mutually exclusive. Microsatellite instability (MSI) was detected in 69% of the examined lymphomas; the percentage of MSI-positive genotypes per tumor ranged from 2% to 12%. The spectrum of genetic alterations detected showed patterns dependent on morphology. Monomorpic ETLs displayed frequently biallelic TCR-gamma gene rearrangement (p = 0078, chi(2) test). They showed a different pattern and fewer allelic imbalances (no 3q27, 4q28, 13q14, fewer 5q21, or 5q33.3-34 aberrations) and a lower frequency of MSI than pleomorphic ETLs.
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PMID:High frequency of genetic aberrations in enteropathy-type T-cell lymphoma. 1456 52

The p53 tumor suppressor protein is a key mediator of an ATM-dependent DNA damage response cascade following cellular exposure to ionizing radiation. The p53-family members, p63 and p73, are highly similar to p53, yet are differentially activated by IR, UV and cis-platinum via ATM and c-abl/ATR signaling pathways. Loss of function of p53 can occur by mutation or degradation; giving rise to alterations in G(1) and G(2) cell cycle checkpoint control, cell death, DNA repair and genetic stability. The end result of these alterations can be the generation of radioresistant mutant tumor cells. Indeed, in isogenic systems, loss of p53 or p73 function has been associated with decreased chemosensitivity and radiosensitivity, in vitro. However, clinical data supporting a role for p53 genotype as an independent predictive factor for radiotherapy outcome continues to be controversial due to variable endpoints in clinical trial design and in methodology in detecting p53 function. Nonetheless, in carefully controlled radiotherapy studies where mutations in p53 have been detected using DNA sequencing or functional assays, the presence of mutant p53 can be associated with decreased local control following radiotherapy. This suggests that novel molecular treatment strategies specifically designed to re-institute normal p53 function within resistant tumors can be used as combined modality protocols to improve local control and maintain a therapeutic ratio. A future challenge lies in the pre-therapy determination of a 'molecular therapeutic ratio' for individual patients which could allow for specific prognostication based on p53 functional status and subsequent individualized therapy.
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PMID:The p53 protein family and radiation sensitivity: Yes or no? 1519 26

The c-abl tyrosine kinase is the proto-oncogene of the v-abl oncogene of the Abelson murine leukemia virus. Although mutational variants of c-Abl can exhibit gain of function and can produce a transformed phenotype, the function of c-Abl in transformation remained unclear. Here, we report that the loss of c-abl facilitates transformation. c-abl-knockout mouse embryonic fibroblasts (MEFs) immortalized by SV40 T antigen acquired anchorage-independent growth, and by constructing mutational variants of T antigen we showed that binding of large T antigen to p53 and RB was necessary to induce anchorage-independent growth. Although c-abl/p53 double-knockout MEFs did not undergo anchorage-independent growth, those expressing human papilloma virus 16 E7, which mainly inactivates RB, did. Our results show that the loss of c-abl facilitates anchorage-independent growth in the context of p53 and RB deficiency, and suggest that loss of function of c-abl facilitates some types of transformation.
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PMID:Loss of c-abl facilitates anchorage-independent growth of p53- and RB- deficient primary mouse embryonic fibroblasts. 1537 21

To understand the role of endogenous p53 and related proteins in pancreatic injury responses, we established primary pancreatic acinar cultures from wild-type and p53-deficient mice and investigated the relationship between apoptosis, proliferation and underlying molecular events in cells exposed to the DNA cross-linking agent cisplatin. This treatment led to a time-dependent elevation in p53 levels, accompanied by phosphorylation at key serine residues. Despite this apparent activation of p53, acinar cells entered growth arrest unaffected by p53 deficiency. Moreover, p53-null cells exhibited only a temporal delay in engaging apoptosis, compared to wild-type counterparts. Whilst p53-proficient cells rapidly accumulated nuclear p21, the kinetics of p21 accumulation in p53-null cells were delayed, correlating with the execution of p53-independent apoptosis. During the course of treatment, c-abl and TAp73alpha, a p53 homologue, accumulated in acinar cell nuclei, irrespective of genotype, indicating that they are induced upon DNA damage and that they may act in parallel or in concert with p53 for the eradication of damaged acinar cells. We also report the nuclear accumulation of c-abl and TAp73alpha in cells, treated with the nuclear export inhibitor leptomycin B, suggesting that these proteins undergo constant nucleocytoplasmic shuttling in normal culture conditions, possibly reflecting a role for TAp73alpha-mediated transactivation or repression in the regulation of in vitro acinar cell growth.
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PMID:Induction of p21 and nuclear accumulation of TAp73alpha and c-abl during apoptosis of cisplatin-treated primary pancreatic acinar cells. 1554 3

Tumour formations arise as a consequence of alterations in the control of cell proliferation as well as with disorders in interactions between cells and their environment that result in invasion and metastasis. Recent advances in understanding the genetic basis of malignant diseases have been dominated by research in colorectal cancer. Genetic alterations of several proto-oncogenes and tumor-suppressor genes (e.g. APC/MCC, RAS, DCC, p53 mutations and/or allelic losses, hyperexpression of c-MYC and RB genes), as well as other genomic alterations, appear at characteristic stages of tumor development and are observed in most neoplasms. Generally, the normal cell has multiple independent mechanisms that regulate its growth and differentiation potential, and several separate events would, therefore, be needed to override these control mechanisms, as well as induce the other aspects of the transformed phenotype, like metastasis. These signals may be either positive or negative, and the acquisition of tumorigenicity results from genetic changes that affect these control points following a multistep mode. Statistics of the frequency of cancer incidence with age in humans indicate that for the genesis of e.g. lung carcinoma, five or six steps are required. Other types of cancers, such as leukemias and sarcomas, probably require quite a different number of rate-limiting changes. One of the best characterized tumours to provide a genetic model is colorectal tumorigenesis. Mutations implicated in breast cancer tumorigenicity are also studied and used as a genetic model in the literature worldwide. Finally, activation of c-abl in chronic myelogenous leukaemia (CML) and acute lymphoblastic leukaemia could also be presented as an example, which provides probably the strongest evidence for the role of proto-oncogenes in human malignancy process.
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PMID:Genetic models of human cancer as a multistep process. Paradigm models of colorectal cancer, breast cancer, and chronic myelogenous and acute lymphoblastic leukaemia. 1647 12


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