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

The nucleolar Arf protein has initially been shown to regulate cell cycle through the so-called Arf-mdm2-p53 pathway. In addition to this well characterized pathway, convergent data published since 2000 indicate that Arf can inhibit cell proliferation in absence of p53, suggesting the existence of a p53-independent pathway. Several partners have recently been described that could participate in an alternative regulatory process. Recent results show that : (1) Arf binds the rDNA promoter to inhibit the transcription of the 47S rRNA precursor and (2) Arf interacts with the nucleophosmin/B23 protein to negatively regulate rRNA maturation, it is assumed that the tumour suppressor may downregulate the cell cycle progression through the control of ribosome biogenesis, thus resulting in completion of cell cycle arrest.
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PMID:[The negative regulation of ribosome biogenesis: a new Arf-dependent pathway controlling cell proliferation?]. 1668 21

The p53/p14ARF/mdm2 stress response pathway plays a central role in mediating cellular responses to oncogene activation, genome instability, and therapy-induced DNA damage. Abrogation of the pathway occurs in most if not all cancers, and may be essential for tumor development. The high frequency with which the pathway is disabled in cancer and the fact that the pathway appears to be incompatible with tumor cell growth, has made it an important point of focus in cancer research and therapeutics development. Recently, Nucleophosmin (NPM, B23, NO38 and numatrin), a multifunctional nucleolar protein, has emerged as a p14ARF binding protein and regulator of p53. While complex formation between ARF and NPM retains ARF in the nucleolus and prevents ARF from activating p53, DNA damaging treatments promote a transient subnuclear redistribution of ARF to the nucleoplasm, where it interacts with mdm2 and promotes p53 activation. The results add support to a recently proposed model in which the nucleolus serves as a p53-uspstream sensor of stress, and where ARF links nucleolar stress signals to nucleoplasmic effectors of the stress response. A better understanding of ARF's nucleolar interactions could further elucidate the regulation of the p53 pathway and suggest new therapeutic approaches to restore p53 function.
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PMID:DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer. 1685 88

The nucleolar Arf protein has been shown to regulate cell cycle through both p53-dependent and -independent pathways. In addition to the well-characterized Arf-mdm2-p53 pathway, several partners of Arf have recently been described that could participate in alternative regulation process. Among those is the nucleolar protein B23/NPM, involved in the sequential maturation of rRNA. p19ARF can interact with B23/NPM in high molecular complexes and partially inhibit the cleavage of the 32S rRNA, whereas the human p14ARF protein has been shown to participate in the degradation of NPM/B23 by the proteasome. These data led to define Arf as a negative regulator of ribosomal RNA maturation. Our recent finding that the human p14ARF protein was able to specifically interact with the rRNA promoter in a p53-independent context, led us to analyse in vitro and in vivo the consequences of this interaction. Luciferase assay and pulse-chase experiments demonstrated that the rRNA transcription was strongly reduced upon p14ARF overexpression. Investigations on potential interactions between p14ARF and the transcription machinery proteins demonstrated that the upstream binding factor (UBF), required for the initiation of the transcriptional complex, was a new partner of the p14ARF protein. We next examined the phosphorylation status of UBF as UBF phosphorylation is required to recruit on the promoter factors involved in the transcriptional complex. Upon p14ARF overexpression, UBF was found hypophosphorylated, thus unable to efficiently recruit the transcription complex. Taken together, these data define a new p53-independent pathway that could regulate cell cycle through the negative control of rRNA transcription.
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PMID:Human tumor suppressor p14ARF negatively regulates rRNA transcription and inhibits UBF1 transcription factor phosphorylation. 1692 43

B23 (nucleophosmin/NPM) is a multifunctional protein that recently has been directly implicated in the p53 network by its documented interaction with the p14(ARF)/p19(Arf) tumor suppressor, a major upstream activator of p53. Here we provide an overview of the functional interactions of B23 and ARF. We also integrate the current models into a unified picture, showing that B23 is essential for stabilizing and maintaining a basal level of ARF in the nucleolus, whereas increasing levels of ARF after oncogenic stress promotes B23 degradation and interferes with B23 nucleocytoplasmic shuttling. In this way, ARF can be regarded as a parasitic peptide on the B23 molecule, because ARF uses this chaperone for its own survival but also antagonizes normal activities of B23. Finally, the functional significance of the ARF-B23 interaction for tumor development and the prospects for novel cancer therapies are evaluated.
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PMID:B23 and ARF: friends or foes? 1694 25

Alterations in the p14(ARF) tumor suppressor are frequent in many human cancers and are associated with susceptibility to melanoma, pancreatic cancer, and nervous system tumors. In addition to its p53-regulatory functions, p14(ARF) has been shown to influence ribosome biogenesis and to regulate the endoribonuclease B23, but there remains considerable controversy about its nucleolar role. We sought to clarify the activities of p14(ARF) by studying its interaction with ribosomes. We show that p14(ARF) and B23 interact within the nucleolar 60 S preribosomal particle and that this interaction does not require rRNA. In contrast to previous reports, we found that expression of p14(ARF) does not significantly alter ribosome biogenesis but inhibits polysome formation and protein translation in vivo. These results suggest a ribosome-dependent p14(ARF) pathway that regulates cell growth and thus complements p53-dependent p14(ARF) functions.
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PMID:Physical and functional interaction of the p14ARF tumor suppressor with ribosomes. 1703 34

Analysis of lung cancer response to chemotherapeutic agents showed the accumulation of a Taxol-induced protein that reacted with an anti-phospho-MEK1/2 antibody. Mass spectroscopy identified the protein as nucleophosmin/B23 (NPM), a multifunctional protein with diverse roles: ribosome biosynthesis, p53 regulation, nuclear-cytoplasmic shuttling, and centrosome duplication. Our work demonstrates that following cellular exposure to mitosis-arresting agents, NPM is phosphorylated and its chromatographic property is altered, suggesting changes in function during mitosis. To determine the functional relevance of NPM, its expression in tumor cells was reduced by siRNA. Cells with reduced NPM were treated with Taxol followed by microarray profiling accompanied by gene/protein pathway analyses. These studies demonstrate several expected and unexpected consequences of NPM depletion. The predominant downstream effectors of NPM are genes involved in cell proliferation, cancer, and the cell cycle. In congruence with its role in cancer, NPM is over-expressed in primary malignant lung cancer tissues. We also demonstrate a role for NPM in the expression of genes encoding SET (TAF1beta) and the histone methylase SET8. Additionally, we show that NPM is required for a previously unobserved G2/M upregulation of TAF1A, which encodes the rDNA transcription factor TAF(I)48. These results demonstrate multi-faceted functions of NPM that can affect cancer cells.
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PMID:Global functional analysis of nucleophosmin in Taxol response, cancer, chromatin regulation, and ribosomal DNA transcription. 1706 96

Mutations leading to aberrant cytoplasmic localization of Nucleophosmin 1 (NPM1) have been recently identified as the most frequent genetic alteration in acute myelogenous leukemia. However, the oncogenic potential of this nucleophosmin mutant (NPMc+) has never been established, which casts doubt on its role in leukemogenesis. By performing classical transformation assays, we find that NPMc+, but not wild-type NPM, cooperates specifically with adenovirus E1A to transform primary mouse embryonic fibroblasts in soft agar. We demonstrate that NPMc+ blocks the p19(Arf) (Arf) induction elicited by E1A. Surprisingly, however, we find that NPMc+ induces cellular senescence and that E1A is able to overcome this response. We propose a model whereby the NPMc+ pro-senescence activity needs to be evaded for oncogenic transformation, even though NPMc+ can concomitantly blunt the Arf/p53 pathway. These findings identify for the first time NPMc+ as an oncogene and shed new unexpected light on its mechanism of action.
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PMID:The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence. 1754 53

EML4-ALK gene fusions have recently been discovered in a subset of human lung carcinomas, and fusions of the ALK tyrosine kinase gene with the NPM, TPM3, CLTC, ATIC, and TFG genes have been found in hematological malignancies. To elucidate the role of fusions between ALK and other genes in pulmonary carcinogenesis, we examined 77 non-small cell lung carcinomas (NSCLCs) for EML4-, NPM-, TPM3-, CLTC-, ATIC-, and TFG-ALK fusion transcripts by RT-PCR and subsequent sequencing analysis. Although no expression of NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts were detected in any of the cases, expression of EML4-ALK fusion transcripts was detected in two (2.6%) of the 77 NSCLCs. In one of the two NSCLCs there was fusion between exon 13 of EML4 and exon 20 of ALK, i.e., variant 1, and in the other there was fusion between exon 20 of EML4 and exon 20 of ALK, i.e., variant 2. Both patients had a history of smoking, and histologically the carcinomas were adenocarcinoma. No somatic mutations were detected in the mutation cluster regions of the EGFR, K-RAS, and PIK3CA genes in these two carcinomas, however, a Pro177Ser mutation of the p53 gene was detected in the carcinoma that contained the variant 1 EML4-ALK fusion transcripts. In situ PCR of a paraffin block section showed that the carcinoma with expression of the variant 1 actually contained an EML4-ALK fusion gene. These results suggested that the EML4-ALK fusion gene product is involved in the carcinogenesis of a subset of NSCLCs.
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PMID:EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. 1824 62

Anaplastic large cell lymphoma (ALCL) is a T/null-cell neoplasm characterized by chromosomal translocations involving the anaplastic lymphoma kinase (ALK) gene (ALK). Tumours with similar morphology and phenotype but negative for ALK have been also recognized. The secondary chromosomal imbalances of these lymphomas are not well known. We have examined 74 ALCL, 43 ALK-positive and 31 ALK-negative, cases by comparative genomic hybridization (CGH), and locus-specific alterations for TP53 and ATM were examined by fluorescence in situ hybridization and real-time quantitative polymerase chain reaction. Chromosomal imbalances were detected in 25 (58%) ALK-positive and 20 (65%) ALK-negative ALCL. ALK-positive ALCL with NPM-ALK or other ALK variant translocations showed a similar profile of secondary genetic alterations. Gains of 17p and 17q24-qter and losses of 4q13-q21, and 11q14 were associated with ALK-positive cases (P = 0.05), whereas gains of 1q and 6p21 were more frequent in ALK-negative tumours (P = 0.03). Gains of chromosome 7 and 6q and 13q losses were seen in both types of tumours. ALCL-negative tumours had a significantly worse prognosis than ALK-positive. However no specific chromosomal alterations were associated with survival. In conclusion, ALK-positive and negative ALCL have different secondary genomic aberrations, suggesting they correspond to different genetic entities.
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PMID:Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas. 1827 29

In post-mitotic neurons, the mechanisms of the apoptotic checkpoint that is activated by DNA damage remain unclear. Here we show that in cultured cortical neurons, the DNA damaging agent camptothecin (CPT) reduced transcription of rRNA and disrupted nucleolar staining for B23/nucleophosmin suggesting DNA damage-induced nucleolar stress. Although CPT activated the pro-apoptotic protein p53, the CPT-induced nucleolar stress was unaffected by p53 inhibition. In addition, brain-derived neurotrophic factor-mediated protection from CPT-induced apoptosis prevented neither nucleolar stress nor p53 activation. Therefore, inhibition of rRNA transcription might be upstream of the pro-apoptotic p53 activity. Indeed, short hairpin RNA-mediated inhibition of a RNA-Polymerase-I co-factor, transcription initiation factor IA, attenuated rRNA transcription causing nucleolar stress and p53-dependent neuronal apoptosis. The protein synthesis inhibitor cycloheximide blocked apoptosis that was induced by over-expressed shTIF-IA or active form of p53. Also, the general transcription inhibitor actinomycin D triggered nucleolar stress and activated p53. However, it did not induce apoptosis except at the low concentration of 0.05 microg/mL with stronger inhibitory activity against nucleolar than extranucleolar transcription. Hence, nucleolar stress-activated apoptosis requires extranucleolar transcription. This study identifies the nucleoli of post-mitotic neurons as sensors of DNA damage coupling reduced rRNA transcription to p53-mediated apoptosis that requires de novo expression of protein-coding genes. Thus, rDNA selectivity of DNA damage may determine its ability to induce neuronal apoptosis.
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PMID:Inhibition of nucleolar transcription as a trigger for neuronal apoptosis. 1831 59


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