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)

Activation of the p53 tumour suppressor protein by distinct forms of stress leads to inhibition of cellular proliferation by inducing cell cycle arrest or apoptosis. The cyclin-dependent kinase inhibitor roscovitine has been shown to induce nuclear accumulation of wild-type p53 in human untransformed and tumour-derived cells. We analyzed the response of different human tumour cell lines to roscovitine treatment with respect to their p53 status. Striking induction of wild-type p53 protein and dramatic enhancement of p53-dependent transcription, coinciding with p21WAF1 induction, was observed in wildtype, but not mutant, p53-bearing tumour cells after treatment with roscovitine. The transcriptional activity of p53 was substantially higher in roscovitine-treated cells than in cells irradiated with ultraviolet C or ionizing radiation, even though all these agents induced a similar amount of p53 accumulation. These results highlight the therapeutic potential of roscovitine as an anticancer drug, especially in tumours retaining a functional wild-type p53 pathway.
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PMID:Potent induction of wild-type p53-dependent transcription in tumour cells by a synthetic inhibitor of cyclin-dependent kinases. 1157 89

The small basic protein p14ARF, encoded by one of the alternative transcripts from the human INK4A/ARF locus, interferes with MDM2-mediated ubiquitination of the p53 tumour suppressor protein. The resultant stabilization of p53 leads to increased expression of p53-regulated genes, such as MDM2 itself and the cyclin-dependent kinase inhibitor p21(CIP1). Here we relate physical interactions between p14ARF and MDM2, as determined using synthetic peptides and systematic deletions of p14ARF, with consequential effects on p53 stabilization and transcriptional activity. The data imply that the amino terminal half of p14ARF, encoded by the alternative first exon (exon 1beta) contacts MDM2 through multiple domains that can independently impede MDM2-mediated degradation of p53, provided that they are localized in the cell nucleus. As well as identifying previously unrecognized functional domains, our findings offer an explanation for the relative paucity of missense mutations in exon 1beta in human tumours.
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PMID:Multiple interacting domains contribute to p14ARF mediated inhibition of MDM2. 1208 28

The p16INK4a gene, localized within chromosome 9p21, has been identified as a cyclin-dependent kinase inhibitor and may negatively regulate the cell cycle acting as a tumour suppressor. Genetic alterations involving the 9p21 region are common in human cancers. Our purpose was to investigate 9p21 LOH and expression of p16 protein and their possible prognostic value in laryngeal cancer. PCR-based techniques were used for investigating 9p21 LOH and immunohistochemical methods for p16 protein expression. 9p21 LOH was detected in 10/41 (24.4%) informative tumours and p16 protein in 11/41 (26.8%). By univariate analysis 9p21 LOH proved to be significantly related to overall survival whereas expression of p16 protein was related with quicker relapse. Analysis of 9p21 LOH enables the assessment of biology of laryngeal cancer and it is a prognostic factor of overall survival. A p16 protein has a prognostic value in assessment of disease free survival in those patients. Although clinical impact of gene and protein p16 in laryngeal cancer is still unclear.
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PMID:[Expression of p16 gene and protein in the evaluation of dynamics of laryngeal cancer growth]. 1510 Dec 77

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

The G1 phase of the cell cycle is characterized by a high rate of membrane phospholipid turnover. Cells regulate this turnover by coordinating the opposing actions of CTP:phosphocholine cytidylyltransferase and the group VI Ca2+-independent phospholipase A2 (iPLA2). However, little is known about how such turnover affects cell-cycle progression. Here, we show that G1-phase phospholipid turnover is essential for cell proliferation. Specific inhibition of iPLA2 arrested cells in the G1 phase of the cell cycle. This G1-phase arrest was associated with marked upregulation of the tumour suppressor p53 and the expression of cyclin-dependent kinase inhibitor p21cip1. Inactivation of iPLA2 failed to arrest p53-deficient HCT cells in the G1 phase and caused massive apoptosis of p21-deficient HCT cells, suggesting that this G1-phase arrest requires activation of p53 and expression of p21cip1. Furthermore, downregulation of p53 by siRNA in p21-deficient HCT cells reduced the cell death, indicating that inhibition of iPLA2 induced p53-dependent apoptosis in the absence of p21cip1. Thus, our study reveals hitherto unrecognized cooperation between p53 and iPLA2 to monitor membrane-phospholipid turnover in G1 phase. Disrupting the G1-phase phospholipid turnover by inhibition of iPLA2 activates the p53-p21cip1 checkpoint mechanism, thereby blocking the entry of G1-phase cells into S phase.
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PMID:Disruption of G1-phase phospholipid turnover by inhibition of Ca2+-independent phospholipase A2 induces a p53-dependent cell-cycle arrest in G1 phase. 1649 6

The p16(INK4a) cyclin-dependent kinase inhibitor has a key role in establishing stable G1 cell-cycle arrest through activating the retinoblastoma (Rb) tumour suppressor protein pRb in cellular senescence. Here, we show that the p16(INK4a) /Rb-pathway also cooperates with mitogenic signals to induce elevated intracellular levels of reactive oxygen species (ROS), thereby activating protein kinase Cdelta (PKCdelta) in human senescent cells. Importantly, once activated by ROS, PKCdelta promotes further generation of ROS, thus establishing a positive feedback loop to sustain ROS-PKCdelta signalling. Sustained activation of ROS-PKCdelta signalling irreversibly blocks cytokinesis, at least partly through reducing the level of WARTS (also known as LATS1), a mitotic exit network (MEN) kinase required for cytokinesis, in human senescent cells. This irreversible cytokinetic block is likely to act as a second barrier to cellular immortalization ensuring stable cell-cycle arrest in human senescent cells. These results uncover an unexpected role for the p16(INK4a)-Rb pathway and provide a new insight into how senescent cell-cycle arrest is enforced in human cells.
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PMID:Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. 1707 52

The cyclin-dependent kinase inhibitor p21WAF1/CIP1, a critical regulator of the cell cycle, is mainly regulated by p53 tumour suppressor at the transcriptional level. Restoration of p21WAF1/Cip1 expression in p53-deficient malignant cells suppress tumour growth. Cyclosporine A (CsA) affects proliferation and survival of cultured malignant glioma cells and impairs growth of experimental gliomas. CsA induced p21WAF1/Cip1 expression de novo in human glioblastoma cells with p53 deficiency. We demonstrate that transcriptional activation of p21WAF1/Cip1 expression correlated with induction of ERK1/2 and c-Jun phosphorylation in CsA-treated glioblastoma cells. Pre-treatment with ERK pathway inhibitors or overexpression of dominant-negative mutants MKK1, ERK2 and c-Jun reduced activation of the p21WAF1/Cip1 promoter. Overexpression of tethered AP-1 dimers containing c-Jun was sufficient to activate the truncated -200 bp p21WAF1/Cip1 promoter, which does not contain p53 binding sites. Chromatin immunoprecipitation revealed that P-c-Jun is bound to the proximal part of p21WAF1/Cip1 promoter in CsA-treated glioblastoma cells. It suggests that CsA activates p53-independent, transcriptional activation p21WAF1/Cip1 expression, mediated by ERK/c-Jun/AP-1 signaling pathway.
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PMID:Alternative pathway of transcriptional induction of p21WAF1/Cip1 by cyclosporine A in p53-deficient human glioblastoma cells. 1732 21

MUC4 is a transmembrane mucin expressed in pancreatic ductal adenocarcinoma (DAC) in contrast to normal pancreas, and is an independent predictor of poor prognosis in patients with invasive DAC. Our aim was therefore to investigate the mechanisms that control MUC4 expression in pancreatic cancer cells. We focused our study on activator protein (AP)-2alpha transcription factor that acts as a tumour suppressor gene in several cancers. In a series of 18 human DAC, using immunohistochemistry, we confirmed that MUC4 was exclusively expressed in cancerous or preneoplastic lesions in 83% of the samples. On the contrary, AP-2 was mainly expressed by non-tumoural ductal cells (61%) or endocrine cells (67%). Moreover, MUC4 and AP-2 were never found co-expressed suggesting an inhibitory role of AP-2alpha in normal ductal cells. In CAPAN-1 and CAPAN-2 cells, transient AP-2alpha over-expression decreased both MUC4 mRNA and apomucin levels by 20-40% by a mechanism involving inhibition of MUC4 promoter. By chromatin immunoprecipitation and gel-shift assays, we demonstrated that this inhibition involved two AP-2 cis-elements located in the -475/-238 region of the promoter. CAPAN-1 clones, which stably over-expressed AP-2alpha, displayed a strong MUC4 down-regulation (-38 to -100%), a significant decrease of both cell proliferation and invasion concomitant to the up-regulation of p27 cyclin-dependent kinase inhibitor. In conclusion, our data provide evidence that AP-2alpha is an important in vivo negative regulator of MUC4 expression in human pancreatic tissue and that AP-2alpha may play a tumour-suppressive role in pancreatic DAC.
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PMID:Transcription factor AP-2alpha represses both the mucin MUC4 expression and pancreatic cancer cell proliferation. 1762 92

We have investigated the frequency of methylation of several tumour suppressor genes in uveal melanoma. As the loss of one copy of chromosome 3 (monosomy 3), which is found in about half of these tumours, is tightly associated with metastatic disease, a special emphasis was laid on genes located on this chromosome, including the fragile histidine triad (FHIT), von Hippel-Lindau (VHL), beta-catenin (CTNNB1), activated leukocyte cell adhesion molecule (ALCAM) and retinoic acid receptor-beta2 (RARB) genes. In addition, the methylation patterns of the CpG-rich regions 5' of the E-cadherin (CDH1), p16/cyclin-dependent kinase inhibitor 2 A (CDKN2A) and retinoblastoma (RB1) genes were analysed by bisulphite genomic sequencing or methylation-specific PCR (MSP). Furthermore, the SNRPN and D15S63 loci, which are located in the imprinted region of chromosome 15, were included in the study. Aberrant methylation was detected in nine of 40 tumours analysed: The imprinted SNRPN and D15S63 loci were hypermethylated in three tumours, all of which retained both copies of chromosome 3. Methylated RARB alleles were detected in three tumours, whereas in three other tumours CDKN2A was found to be methylated. As we did not find RARB and CDKN2A preferentially methylated in tumours with monosomy 3, which is a significant predictor of metastatic disease, we suggest that these genes may play a causative role in the formation of uveal melanoma but not in the development of metastases.
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PMID:Methylation analysis of several tumour suppressor genes shows a low frequency of methylation of CDKN2A and RARB in uveal melanomas. 1862 84

JunB is a member of the AP-1 (activator protein-1) family of dimeric transcription factors. It exerts a dual action on the cell cycle. It is best known as a cell proliferation inhibitor, a senescence inducer and a tumour suppressor. As for the molecular mechanisms involved, they largely involve both positive actions on genes such as the p16INK4alpha cyclin-dependent kinase inhibitor and negative effects on genes such as cyclin D1 during the G1-phase of the cell cycle. However, JunB is also endowed with a cell-division-promoting activity, in particular via stimulation of cyclin A2 gene expression during S-phase. Strikingly, its role in G2 and M has received little attention so far despite its possible role in the preparation of mitosis. This review addresses the known and possible mechanisms whereby JunB is implicated in the control of the different phases of the cell cycle.
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PMID:Regulation and function of JunB in cell proliferation. 1879 52


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