Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumour suppressor ARF (alternative reading frame) is encoded by the INK4a (inhibitor of cyclin-dependent kinase 4)/ARF locus, which is frequently altered in human tumours. ARF binds MDM2 (murine double minute 2) and releases p53 from inhibition by MDM2, resulting in stabilization, accumulation and activation of p53. Recently, ARF has been found to associate with other proteins, but, to date, little is known about ARF-associated proteins that are implicated in post-translational regulation of ARF activity. Using a yeast two-hybrid screen, we have identified a novel protein, LZAP (LXXLL/leucine-zipper-containing ARF-binding protein), that interacts with endogenous ARF in mammalian cells. In the present study, we show that LZAP reversed the ability of ARF to inhibit HDM2's ubiquitin ligase activity towards p53, but simultaneously co-operated with ARF, maintaining p53 stability and increasing p53 transcriptional activity. Expression of LZAP, in addition to ARF, increased the percentage of cells in the G1 phase of the cell cycle. Expression of LZAP also caused activation of p53 and a p53-dependent G1 cell-cycle arrest in the absence of ARF. Taken together, our data suggest that LZAP can regulate ARF biochemical and biological activity. Additionally, LZAP has p53-dependent cell-cycle effects that are independent of ARF.
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PMID:A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2. 1617 22

Inactivation of p53 and p73 is known to promote thyroid cancer progression. We now describe p63 expression and function in human thyroid cancer. TAp63alpha is expressed in most thyroid cancer specimens and cell lines, but not in normal thyrocytes. However, in thyroid cancer cells TAp63alpha fails to induce the target genes (p21Cip1, Bax, MDM2) and, as a consequence, cell cycle arrest and apoptosis occur. Moreover, TAp63alpha antagonizes the effect of p53 on target genes, cell viability and foci formation, and p63 gene silencing by small interfering (si) RNA results in improved p53 activity. This unusual effect of TAp63alpha depends on the protein C-terminus, since TAp63beta and TAp63gamma isoforms, which have a different arrangement of their C-terminus, are still able to induce the target genes and to exert tumour-restraining effects in thyroid cancer cells. Our data outline the existence of a complex network among p53 family members, where TAp63alpha may promote thyroid tumour progression by inactivating the tumour suppressor activity of p53.
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PMID:The p53-homologue p63 may promote thyroid cancer progression. 1632 35

A number of proteins are activated by stress stimuli but none so spectacularly or with the degree of complexity as the tumour suppressor p53 (human p53 gene or protein). Once stabilized, p53 is responsible for the transcriptional activation of a series of proteins involved in cell cycle control, apoptosis and senescence. This protein is present at low levels in resting cells but after exposure to DNA-damaging agents and other stress stimuli it is stabilized and activated by a series of post-translational modifications that free it from MDM2 (mouse double minute 2 but used interchangeably to denote human also), a ubiquination ligase that ubiquitinates it prior to proteasome degradation. The stability of p53 is also influenced by a series of other interacting proteins. In this review, we discuss the post-translational modifications to p53 in response to different stresses and the consequences of these changes.
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PMID:The complexity of p53 stabilization and activation. 1660 50

Recent studies have shown that the G-allele of MDM2 SNP309 (T/G) in the p53 tumour suppressor pathway can accelerate tumorigenesis and alter the risk of various cancers in women and not in men. In this report, data are presented from two independent groups of patients that suggest that the G-allele of SNP309 accelerates colorectal tumour formation only in women, and that lend further support to the model that primarily female-specific hormones, such as oestrogen, could either directly or indirectly allow for the G-allele of SNP309 to accelerate tumour formation in women.
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PMID:MDM2 SNP309 accelerates colorectal tumour formation in women. 1682 30

Mammalian cells that sustain oncogenic insults can invoke defensive programmes that either halt their division or trigger their apoptosis, but these countermeasures must be finely tuned to discriminate between physiological and potentially harmful growth-promoting states. By functioning specifically to oppose abnormally prolonged and sustained proliferative signals produced by activated oncogenes, the ARF tumour suppressor antagonizes functions of MDM2 to induce protective responses that depend on the p53 transcription factor and its many target genes. However, ARF has been reported to physically associate with proteins other than MDM2 and to have p53-independent activities, most of which remain controversial and poorly understood.
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PMID:Divorcing ARF and p53: an unsettled case. 1691 96

Mutations in TP53, the gene that encodes the tumour suppressor p53, are found in 50% of human cancers, and increased levels of its negative regulators MDM2 and MDM4 (also known as MDMX) downregulate p53 function in many of the rest. Understanding p53 regulation remains a crucial goal to design broadly applicable anticancer strategies based on this pathway. This Review of in vitro studies, human tumour data and recent mouse models shows that p53 post-translational modifications have modulatory roles, and MDM2 and MDM4 have more profound roles for regulating p53. Importantly, MDM4 emerges as an independent target for drug development, as its inactivation is crucial for full p53 activation.
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PMID:Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. 1712 9

The tumour suppressor genes, TP53 and RB1, and four genes involved in their regulation, INK4a, ARF, MDM2 and MDMX, were analysed in a series of 36 post-radiotherapy radiation-induced sarcomas. One-third of the tumours developed in patients carrying a germline mutation of RB1 that predisposed them to retinoblastoma and radiation-induced sarcomas. The genetic inactivation of RB1 and/or TP53 genes was frequently observed in these sarcomas. These inactivations were owing to an interplay between point mutations and losses of large chromosome segments. Radiation-induced somatic mutations were observed in TP53, but not in RB1 or in the four other genes, indicating an early role of TP53 in the radio-sarcomagenesis. RB1 and TP53 genes were biallelically coinactivated in all sarcomas developing in the context of the predisposition, indicating that both genes played a major role in the formation of these sarcomas. In the absence of predisposition, TP53 was biallelically inactivated in one-third of the sarcomas, whereas at least one allele of RB1 was wild type. In both genetic contexts, the TP53 pathway was inactivated by genetic lesions and not by the activation of the ARF/MDM2/MDMX pathway, as recently shown in retinoblastomas. Together, these findings highlight the intricate tissue- and aetiology-specific relationships between TP53 and RB1 pathways in tumorigenesis.
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PMID:RB1 and TP53 pathways in radiation-induced sarcomas. 1736 43

The tumour suppressor protein ARF provides a defence mechanism against hyperproliferative stresses that can result from the aberrant activation of oncogenes. Accordingly, ARF is silenced or deleted in many human cancers. Activation of ARF can arrest growth and cell cycle progression, or trigger apoptosis. A principle mediator of these effects is p53, which ARF stabilizes by binding and inhibiting MDM2. However, ARF has additional targets and remains able to block growth in the absence of p53, albeit less efficiently. For example, ARF can suppress rRNA production in a p53-independent manner. We have found that the synthesis of tRNA by RNA polymerase III is also inhibited in response to ARF. However, in contrast to its effects on rRNA synthesis, ARF is unable to inhibit tRNA gene transcription when p53 is ablated. These results add to the growing list of cellular changes that can be triggered by ARF induction.
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PMID:RNA polymerase III transcription is repressed in response to the tumour suppressor ARF. 1743 68

ZBTB7A (Pokemon) is a member of the POK family of transcriptional repressors. Its main function is the suppression of the p14ARF tumour suppressor gene. Although ZBTB7A expression has been found to be increased in various types of lymphoma, there are no reports dealing with its expression in solid tumours. Given that p14(ARF) inhibits MDM2, the main negative regulator of p53, we hypothesized that overexpression of ZBTB7A could lead indirectly to p53 inactivation. To this end, we examined the status of ZBTB7A and its relationship with tumour kinetics (proliferation and apoptosis) and nodal members of the p53 network in a panel of 83 non-small cell lung carcinomas (NSCLCs). We observed, in the majority of the samples, prominent expression of ZBTB7A in the cancerous areas compared to negligible presence in the adjacent normal tissue elements. Gene amplification (two- to five-fold) was found in 27.7% of the cases, denoting its significance as a mechanism driving ZBTB7A overproduction in NSCLCs. In the remaining non-amplified group of carcinomas, analysis of the mRNA and protein expression patterns suggested that deregulation at the transcriptional and post-translational level accounts for ZBTB7A overexpression. Proliferation was associated with ZBTB7A expression (p = 0.033) but not apoptosis. The association with proliferation was reflected in the positive correlation between ZBTB7A expression and tumour size (p = 0.018). The overexpression of ZBTB7A in both p53 mutant and p53 wild-type cases, implies either a synergistic effect or that ZBTB7A exerts its oncogenic properties independently of the p14(ARF)-MDM2-p53 axis. The concomitant expression of ZBTB7A with p14(ARF) (p = 0.039), instead of the anticipated inverse relation, supports the latter notion. In conclusion, regardless of the pathway followed, the distinct expression of ZBTB7A in cancerous areas and the association with proliferation and tumour size pinpoints a role for this novel cell cycle regulator in the pathogenesis of lung cancer.
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PMID:Gene amplification is a relatively frequent event leading to ZBTB7A (Pokemon) overexpression in non-small cell lung cancer. 1790 53

The p53 protein is well-known for its tumour suppressor function. The p53-MDM2 negative feedback loop constitutes the core module of a network of regulatory interactions activated under cellular stress. In normal cells, the level of p53 proteins is kept low by MDM2, i.e. MDM2 negatively regulates the activity of p53. In the case of DNA damage, the p53-mediated pathways are activated leading to cell cycle arrest and repair of the DNA. If repair is not possible due to excessive damage, the p53-mediated apoptotic pathway is activated bringing about cell death. In this paper, we give an overview of our studies on the p53-MDM2 module and the associated pathways from a systems biology perspective. We discuss a number of key predictions, related to some specific aspects of cell cycle arrest and cell death, which could be tested in experiments.
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PMID:The p53-MDM2 network: from oscillations to apoptosis. 1791 40


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