Increased activity of p53 in senescing fibroblasts.

Atadja, Peter; Wong, Howard; Garkavtsev, Igor; Veillette, Claude; Riabowol, Karl

doi:10.1073/pnas.92.18.8348

Cited by 284 publications

(215 citation statements)

References 43 publications

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“…Several groups have demonstrated that senescent cells arrest with a G1 DNA content, and express increased levels of p16, p21 and p53 (Hara et al, 1996;Alcorta et al, 1996;Rezniko et al, 1996;Atadja et al, 1995;Serrano et al, 1997). p16 accumulates both in ®broblasts and uroepithelial cells as a consequence of the increasing number of population doublings, eventually leading to senescence.…”

Section: Discussionmentioning

confidence: 99%

Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence

Erickson¹,

Sangfelt²,

Heyman³

et al. 1998

Oncogene

104

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Little is known about the molecular background to senescence in T-lymphocytes. In ®broblast systems replicative senescence has been shown to correlate with a number of changes in the expression of the proteins normally regulating progression through the G1 phase of the cell cycle, and recently the Ink4 inhibitor p16 was implicated as a central regulator of replicative senescence in human ®broblasts. It has, however, been claimed that p16 is not expressed in T-lymphocytes. In the present study we have analysed G1 regulating proteins in ageing human T-lymphocytes. We show that PHA and IL-2 stimulated T-lymphocytes cease to proliferate after around 20 population doublings, these cells can not thereafter be restimulated to growth, and were also found to exhibit markers for senescence. We found that Tlymphocytes accumulate p16 and p15 protein during successive population doublings and display high levels of these proteins as they enter into replicative senescence. There was also an increased binding of p16 to the Cdk6 kinase in senescent cells, and a decreased Cdk6 as well as Cdk2 kinase activity. The levels of other G1 regulating proteins were also altered in the senescent cells, such as slightly elevated levels of p21/WAF1, and downregulation of Cdk2 and cyclinD3. The levels of p27/ Kip1 is down regulated in proliferating cells but rise to approximately 15% of the levels in un-stimulated quiescent cells. As a high proportion of T-cell childhood acute lymphoblastic leukaemias have deletions of both p15 and p16, our data suggest that inactivation of these genes makes it possible for leukemic cells to avoid senescence.

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Section: Discussionmentioning

confidence: 99%

Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence

Erickson¹,

Sangfelt²,

Heyman³

et al. 1998

Oncogene

104

View full text Add to dashboard Cite

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“…We also performed p53 dependent reporter assays in NIH 3T3 and NIH 3T3/mot-2 cells. The activity of the full length p21 WAF1 promoter reporter plasmid was three-five fold high in NIH 3T3 cells in different experiments [22], [25] and data not shown]. This suggested that the high level of p21 WAF1 transcript in NIH 3T3/mot-2 cells is either regulated by elements located further upstream to the 2501 bp in the promoter used in the reporter plasmid or by post-transcriptional mechanism(s).…”

Section: Nih 3t3/mot-2 Cells Show An Upregulation Of P21waf1 Expressionmentioning

confidence: 90%

“…This was contrary to the inactivation of p53 function by mot-2 [22], [25]. We first ascertained that the band detected on Western blot was indeed p21 WAF1 by using serially passaged normal mouse embryonic fibroblasts (CMEF) and NIH 3T3 cells cultured at different density ( Fig 1A).…”

Section: Nih 3t3/mot-2 Cells Show An Upregulation Of P21waf1 Expressionmentioning

confidence: 95%

“…Consistent with Western blot analysis, a high level of transcript was apparent in NIH 3T3/mot-2 cells (Fig 1B) implementing that in these cells upregulation of p21 WAF1 occurred at transcriptional level. Since these cells show inactivation of p53 function [22], [25], it is likely that upregulation of p21 WAF1 occurred either by p53-independent pathway or involves post-transcriptional mechanisms. We also performed p53 dependent reporter assays in NIH 3T3 and NIH 3T3/mot-2 cells.…”

Section: Nih 3t3/mot-2 Cells Show An Upregulation Of P21waf1 Expressionmentioning

confidence: 99%

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p53-independent upregulation of p21WAF1 in NIH 3T3 cells malignantly transformed by mot-2

Takano

Wadhwa²,

Mitsui

et al. 2001

Cell Res

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Mot-2 protein is shown to interact with p53 and inhibit its transcriptional activation function. Mot-2 overexpressing stable clones of NIH 3T3 cells were malignantly transformed, however, they had a high level of expression of a p53 downstream gene, p21 WAF1 . The present study was undertaken to elucidate possible molecular mechanism(s) of such upregulation. An increased level of p21 WAF1 expression was detected in stable transfectants although an exogenous reporter gene driven by p21 WAF1 promoter exhibited lower activity in these cells suggesting that some post-transcriptional mechanism contributes to upregulation. Western analyses of transient and stable clones revealed that upregulation of p21 WAF1 in stable NIH 3T3/mot-2 cells may be mediated by cyclin D1 and cdk-2.

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“…However, many other functions have also been reported including roles in differentiation 119 and senescence. 120 Alternatively, normal p53 may suppress inappropriate angiogenesis through transcriptional regulation of fibroblast growth factor (FGF-2), 121 thrombospondin 122 and vascular endothelial growth factor. 122,123 Normal p53 protein has a very short half-life within cells, whereas mutated p53 protein commonly has a prolonged half-life and is detectable by immunohistochemistry.…”

Section: P53 Tsgmentioning

confidence: 99%

Molecular biology of prostate cancer

Karayi

Markham

2004

Prostate Cancer Prostatic Dis

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Development of any cancer reflects a progressive accumulation of alterations in various genes. Oncogenes, tumour suppressor genes, DNA repair genes and metastasis suppressor genes have been investigated in prostate cancer. Here, we review current understanding of the molecular biology of prostate cancer. Detailed understanding of the molecular basis of prostate cancer will provide insights into the aetiology and prognosis of the disease, and suggest avenues for therapeutic intervention in the future.

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Increased activity of p53 in senescing fibroblasts.

Cited by 284 publications

References 43 publications

Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence

Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence

p53-independent upregulation of p21WAF1 in NIH 3T3 cells malignantly transformed by mot-2

Molecular biology of prostate cancer

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