Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase Pim-1 has been implicated in the development of hematopoietic and prostatic malignancies. Here, we present the evidence that two isoforms, the 44 and 33 kDa Pim-1, are expressed in all human prostate cancer cell lines examined. The subcellular localization of human 44 kDa Pim-1 is primarily on the plasma membrane, while the 33 kDa isoform is present in both the cytosol and nucleus in PCA cells. The 44 kDa Pim-1 contains the proline-rich motif at the N-terminus and directly binds to the SH3 domain of tyrosine kinase Etk. Such interaction leads to the activation of Etk kinase activity possibly by competing with the tumor suppressor p53. This is corroborated by the fact that overexpression of the 44 kDa Pim-1 in prostate cancer cells confers the resistance to chemotherapeutic drugs. Our results suggest that these two isoforms of Pim-1 kinase may regulate distinct substrates and the 44 kDa Pim-1 may play a more prominent role in drug resistance in prostate cancer cells.
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PMID:The 44 kDa Pim-1 kinase directly interacts with tyrosine kinase Etk/BMX and protects human prostate cancer cells from apoptosis induced by chemotherapeutic drugs. 1618 5

Transactivation domain (TAD)-truncated p73, DeltaNp73, associates with p53, resulting in suppression of p53's functions. Using p53 null cell lines, we examined whether or not DeltaNp73 can regulate gene expression in a p53-independent manner. When DeltaNp73alpha was co-transfected with a luciferase reporter plasmid with various enhancer elements, NFkappaB-responsive luciferase gene expression was selectively up-regulated by DeltaNp73alpha, but not by other p73-isoforms with TAD and DeltaNp73beta. Deletion of the TAD endowed p73alpha with the ability to enhance the responsive gene's expression, but deletion of the N-terminal proline-rich domain (PRD) rendered the TAD-deleted p73alpha inactive. Considering the inability of DeltaNp73beta, which is the C-terminus-truncated form of DeltaNp73alpha, to function, these results indicate that both the PRD and C-terminus are necessary for DeltaNp73alpha to can activate NFkappaB-responsive luciferase expression. Over-expression of p53 suppressed the TAD-truncated p73alpha-mediated luciferase expression, suggesting that p53 interferes with the TAD-truncated p73alpha-mediated activation of NFkappaB. Inhibitors for NFkappaB activation reduced the TAD-truncated p73alpha-dependent NFkappaB-responsive gene expression, indicating that TAD-truncated p73alpha activates NFkappaB as does TNFalpha. In addition to the results obtained in the reporter gene assay, TAD-truncated p73alpha stimulated the translocation of NFkappaB to the nucleus and the expression of an endogenous NFkappaB-responsive gene, Bcl-XL. Taken together, these results demonstrate that TAD-truncated p73alpha can activate NFkappaB.
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PMID:Up-regulation of NFkappaB-responsive gene expression by DeltaNp73alpha in p53 null cells. 1643 Aug 84

Several kinds of the p53 transcripts in which their open reading frames (ORFs) were truncated (ranging from 101 to 765 bp) were identified in Marek's disease (MD)-derived tumor cell lines as well as avian leukosis- and reticuloendotheliosis-derived ones, detected by nested RT-PCR and subsequent nucleotide sequence analysis. In these ORFs, regions encoding the proline-rich and DNA-binding domains of the p53 protein were frequently deleted, and many of these deletions were found to cause frame shift. Western blot analysis using anti-p53 monoclonal antibodies revealed that multiple p53 isoform proteins with various molecular weights including 45-46, 35 and 28 kDa were expressed in these tumor cell lines, though the p53 protein with a molecular weight of 49 kDa was detected in chicken embryo fibroblasts transformed by the SV40 T antigen as a control. Since no deletions were found in the p53 gene of these MD tumor cell lines, truncations in the p53 ORFs observed in this study might result from alternative splicing of the p53 gene.
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PMID:The presence of the p53 transcripts with truncated open reading frames in Marek's disease tumor-derived cell lines. 1644 98

One of the most frequently mutated genes in human cancers, tumour suppressor p53 (TP53), can induce cell-cycle arrest and apoptosis. The apoptotic function of p53 is tightly linked to its tumour-suppression function and the efficacy of many cancer therapies depends on this. The identification of a new family of proteins, known as ASPPs (ankyrin-repeat-, SH3-domain- and proline-rich-region-containing proteins), has led to the discovery of a novel mechanism that selectively regulates the apoptotic function, but not the cell-cycle-arrest function, of p53, and gives an insight into how p53 responds to different stress signals. ASPPs might be new molecular targets for cancer therapy.
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PMID:ASPP [corrected] and cancer. 1649 44

The mechanisms by which Mdm2 and Mdm4 (MdmX) regulate p53 remain controversial. We generated a mouse encoding p53 lacking the proline-rich domain (p53DeltaP). p53DeltaP exhibited increased sensitivity to Mdm2-dependent degradation and decreased transactivation capacity, correlating with deficient cell cycle arrest and reduced apoptotic responses. p53DeltaP induced lethality in Mdm2-/- embryos, but not in Mdm4-/- embryos. Mdm4 loss did not alter Mdm2 stability but significantly increased p53DeltaP transactivation to partially restore cycle control. In contrast, decreasing Mdm2 levels increased p53DeltaP levels without altering p53DeltaP transactivation. Thus, Mdm4 regulates p53 activity, while Mdm2 mainly controls p53 stability. Furthermore, Mdm4 loss dramatically improved p53DeltaP-mediated suppression of oncogene-induced tumors, emphasizing the importance of targeting Mdm4 in chemotherapies designed to activate p53.
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PMID:A mouse p53 mutant lacking the proline-rich domain rescues Mdm4 deficiency and provides insight into the Mdm2-Mdm4-p53 regulatory network. 1661 33

Increased expression of p202 protein (encoded by the Ifi202 gene) in splenocytes derived from B6.Nba2 mice (congenic for the Nba2 interval derived from the New Zealand Black mice) was correlated with defects in apoptosis of splenic B cells and increased susceptibility to develop systemic lupus erythematosus. We have now investigated the molecular mechanisms by which increased expression of p202 in B6.Nba2 cells contributes to defects in apoptosis. In this study, we report that increased expression of p202 in the B6.Nba2 splenocytes, as compared with cells derived from the parental C57BL/6 (B6) mice, was correlated with increased levels of p53 protein and inhibition of p53-mediated transcription of target genes that encode proapoptotic proteins. Conversely, knockdown of p202 expression in B6.Nba2 cells resulted in stimulation of p53-mediated transcription. We found that p202 bound to p53 in the N-terminal region (aa 44-83) comprising the proline-rich region that is important for p53-mediated apoptosis. Consistent with the binding of p202 to p53, increased expression of p202 in B6.Nba2 mouse embryonic fibroblasts inhibited UV-induced apoptosis. Taken together, our observations support the idea that increased expression of p202 in B6.Nba2 mice increases the susceptibility to develop lupus, in part, by inhibiting p53-mediated apoptosis.
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PMID:Increased expression of Ifi202, an IFN-activatable gene, in B6.Nba2 lupus susceptible mice inhibits p53-mediated apoptosis. 1667 Feb 93

iASPP is one of the most evolutionarily conserved inhibitors of p53, whereas ASPP1 and ASPP2 are activators of p53. We show here that, in addition to the DNA-binding domain, the ASPP family members also bind to the proline-rich region of p53, which contains the most common p53 polymorphism at codon 72. Furthermore, the ASPP family members, particularly iASPP, bind to and regulate the activity of p53Pro72 more efficiently than that of p53Arg72. Hence, escape from negative regulation by iASPP is a newly identified mechanism by which p53Arg72 activates apoptosis more efficiently than p53Pro72.
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PMID:iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53. 1696 64

The stability and activity of tumor suppressor p53 are tightly regulated and partially depend on the p53 proline-rich domain (PRD). We recently analyzed mice expressing p53 with a deletion of the PRD (p53(DeltaP)). p53(DeltaP), a weak transactivator hypersensitive to Mdm2-mediated degradation, is unable to suppress oncogene-induced tumors. This phenotype could result from the loss of two motifs: Pin1 sites proposed to influence p53 stabilization and PXXP motifs proposed to mediate protein interactions. We investigated the importance of these motifs by generating mice encoding point mutations in the PRD. p53(TTAA) contains mutations suppressing all putative Pin1 sites in the PRD, while p53(AXXA) lacks PXXP motifs but retains one intact Pin1 site. Both mutant proteins accumulated in response to DNA damage, although the accumulation of p53(TTAA) was partially impaired. Importantly, p53(TTAA) and p53(AXXA) are efficient transactivators and potent suppressors of oncogene-induced tumors. Thus, Pin1 sites in the PRD may modulate p53 stability but do not significantly affect function. In addition, PXXP motifs are not essential, but structure dictated by the presence of prolines, PXXXXP motifs that may mediate protein interactions, and/or the length of this region appears to be functionally significant. These results may explain why the sequence of the p53 PRD is so variable in evolution.
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PMID:Mouse mutants reveal that putative protein interaction sites in the p53 proline-rich domain are dispensable for tumor suppression. 1715 31

iASPP is an inhibitory member of ASPP (apoptosis stimulating protein of p53, or Ankyrin repeats, SH3 domain and proline-rich region contain Protein) family. As reported previously, it at least includes two isoforms, one is iASPP/RAI (351 amino acids, aa) and the other is iASPP (828 aa).Here, we identified a novel open reading frame of human iASPP, which encodes a 407 aa protein and highly matches with the C terminus of iASPP (828 aa, CAI60219). Hereafter, iASPP (407 aa) will be referred to as iASPP-SV (iASPP splice variant). In further study, we found that iASPP-SV is a nuclear protein, and is capable of binding to p53 in vivo. Moreover, overexpression of iASPP-SV can inhibit the transcriptional activity of p53 on the promoters of both Bax and p21.
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PMID:Identification of a novel isoform of iASPP and its interaction with p53. 1739 96

The Kaposi's sarcoma-associated herpesvirus open reading frame 50 (ORF50) protein (called Rta), is necessary and sufficient for reactivation of the virus from latency. We previously demonstrated that a truncated mutant of ORF50 lacking its C-terminal transcriptional activation domain, called ORF50DeltaSTAD, formed mixed multimers with wild-type (WT) ORF50 and functioned as a dominant negative inhibitor of reactivation. For this report, we investigated the requirements for multimerization of ORF50/Rta in transactivation and viral reactivation. We analyzed multimerization of WT, mutant, and chimeric ORF50 proteins, using Blue Native polyacrylamide gel electrophoresis and size exclusion chromatography. WT and mutant ORF50 proteins form tetramers and higher-order multimers, but not monomers, in solution. The proline-rich, N-terminal leucine heptapeptide repeat (LR) of ORF50 (amino acids [aa] 244 to 275) is necessary but not sufficient for oligomer formation and functions in concert with the central portion of ORF50/Rta (aa 245 to 414). The dominant negative mutant ORF50DeltaSTAD requires the LR to form mixed multimers with WT ORF50 and inhibit its function. In the context of the WT ORF50/Rta protein, mutagenesis of the LR, or replacement of the LR by heterologous multimerization domains from the GCN4 or p53 proteins, demonstrates that tetramers of Rta are sufficient for transactivation and viral reactivation. Mutants of Rta that are unable to form tetramers but retain the ability to form higher-order multimers are reduced in function or are nonfunctional. We concluded that the proline content, but not the leucine content, of the LR is critical for determining the oligomeric state of Rta.
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PMID:Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 ORF50/Rta lytic switch protein functions as a tetramer. 1739 67


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