Comparative study of the expression of Rb and p53 genes in human colorectal cancers, colon carcinoma cell lines and synchronized human fibroblasts

Gope, Mohan L.; Chun, Melanie; Gope, Rajalakshmi

doi:10.1007/bf02424576

Cited by 20 publications

(15 citation statements)

References 36 publications

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“…Our results clearly demonstrate that p53 regulation may occur at a pretranslational step, involving either an increase in p53 gene expression and/or stabilization of its mRNA. Our findings confirm earlier reports, which showed an elevated level ofp53 transcripts in 28 (Gope et al, 1991) and 25 (Lothe et al, 1992) cases, 70% and 66% of tested tumours overexpressed p53 respectively. In these studies, p53 mRNA quantification was performed by Northern blot analysis.…”

Section: Discussionsupporting

confidence: 93%

Overexpression of p53 mRNA in colorectal cancer and its relationship to p53 gene mutation

el-Mahdani

Vaillant²,

Guiguet³

et al. 1997

Br J Cancer

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We analysed the frequency of p53 mRNA overexpression in a series of 109 primary colorectal carcinomas and its association with p53 gene mutation, which has been correlated with short survival. Sixty-nine of the 109 cases (63%) demonstrated p53 mRNA overexpression, without any correlation with stage or site of disease. Comparison with p53 gene mutation indicated that, besides cases in which p53 gene mutation and p53 mRNA overexpression were either both present (40 cases) or both absent (36 cases), there were also cases in which p53 mRNA was overexpressed in the absence of any mutation (29 cases) and those with a mutant gene in which the mRNA was not overexpressed (four cases). Moreover, the mutant p53 tumours exhibited an increase of p53 mRNA expression, which was significantly higher in tumours expressing the mutated allele alone than in tumours expressing both wild- and mutated-type alleles. These data (1) show that p53 mRNA overexpression is a frequent event in colorectal tumours and is not predictive of the status of the gene, i.e. whether or not a mutation is present; (2) provide further evidence that p53 protein overexpression does not only result from an increase in the half-life of mutated p53 and suggest that inactivation of the p53 function in colorectal cancers involves at least two distinct mechanisms, including p53 overexpression and/or mutation; and (3) suggest that p53 mRNA overexpression is an early event, since it is not correlated with Dukes stage.

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Section: Discussionsupporting

confidence: 93%

Overexpression of p53 mRNA in colorectal cancer and its relationship to p53 gene mutation

el-Mahdani

Vaillant²,

Guiguet³

et al. 1997

Br J Cancer

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“…Abundant functionally defective mutant protein might be produced in the tumor cells, but their significance to the clinical outcomes is not clear yet [33, 34]. The significance of increased expression of functionally intact tumor suppressor proteins such as p16 and RB1 in malignant cells remains poorly understood but might be explained by the concept of the cellular homeostasis in the cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Alteredp16INK4and RB1 Expressions Are Associated with Poor Prognosis in Patients with Nonsmall Cell Lung Cancer

Zhao

Huang

Otterson

et al. 2012

Journal of Oncology

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p16INK4 and RB1 are two potent cell cycle regulators to control the G1/S transition by interacting with CDK4/6, E2F, and D-type cyclins, respectively. Depending on the tumour type, genetic alterations resulting in the functional inactivation have frequently been reported in both genes. By contrast, much less is known regarding the overexpression of these proteins in the tumor cells. In this study, expressions of p16INK4 RB1, and CDKN2A copy number variances (CNV) in the tumor cells were assessed by immunohistochemistry and fluorescence in situ hybridization (FISH), respectively, in 73 nonsmall cell lung cancer (NSCLC) with known 5-year survivals. The histologic type (P = 0.01), p16INK4 (P = 0.004), and RB1 (P < 0.001) were predictive of survivals. The CDKN2A CNV (P < 0.05) was also significant when compared to those cases without CNV. Therefore, among the molecular genetic prognostic factors, expressions of RB1 and p16INK4 in the tumor cells were the most strongly predictive of adverse outcomes in stage I and II nonsquamous NSCLC.

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“…To establish a correlation between G1 progression, CDK2 activity, and Hi phosphorylation, we employed W138 human diploid lung fibroblasts, which can be highly synchronized by serum starvation followed by readdition (25)(26)(27)). In the experiments described here, WI38 cells were starved of serum for 72 hr before the readdition of serum to a final concentration of 15%.…”

Section: Resultsmentioning

confidence: 99%

Increased histone H1 phosphorylation and relaxed chromatin structure in Rb-deficient fibroblasts.

Herrera

Chen

Weinberg

1996

Proc. Natl. Acad. Sci. U.S.A.

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Fibroblasts derived from embryos homozygous for a disruption of the retinoblastoma gene (Rb) exhibit a shorter G1 than their wild-type counterparts, apparently due to highly elevated levels of cyclin E protein and deregulated cyclin-dependent kinase 2 (CDK2) activity. Here we demonstrate that the Rb-'-fibroblasts display higher levels of phosphorylated Hi throughout G1 with the maximum being 10-fold higher than that of the Rb+1+ fibroblasts. This profile of intracellular Hi phosphorylation corresponds with deregulated CDK2 activity observed in in vitro assays, suggesting that CDK2 may be directly responsible for the in vivo phosphorylation of Hi. Hi phosphorylation has been proposed to lead to a relaxation of chromatin structure due to a decreased affinity of this protein for chromatin after phosphorylation.In accord with this, chromatin from the Rb-'-cells is more susceptible to micrococcal nuclease digestion than that from Rb+/+ fibroblasts. Increased HI phosphorylation and relaxed chromatin structure have also been observed in cells expressing several oncogenes, suggesting a common mechanism in oncogene and tumor suppressor gene function. pRb, the product of the retinoblastoma susceptibility gene (Rb), is functionally inactivated late in the G1 phase of the cell cycle, a step that is crucial for progression into S phase (1). This inactivation occurs as a consequence of the phosphorylation of pRb by cyclin-dependent kinases (CDKs) in association with their regulatory cyclin subunits (2-4). In particular, cyclin D/CDK4,6 complexes and cyclin E/CDK2 complexes, all of which are active late in Gl, have been shown to phosphorylate pRb in cells after their ectopic expression and in vitro. This phosphorylation of pRb late in G, prevents the protein from binding to various cellular transcription factors (1). Recently, it has been shown that cyclin D/CDK4,6 activity is not required in cells lacking pRb function (5-7), suggesting that the major function of these regulatory proteins is the phosphorylation of pRb.In addition to serving as a substrate for cyclin/CDKs, pRb also regulates expression of cyclin E through transcriptional repression of the cyclin E promoter (8-10). Thus, we have observed that primary mouse embryo fibroblasts lacking a functional Rb gene display elevated cyclin E protein levels and CDK2 activities (9). This may explain the shortened G, of these mutant cells (9, 11), since the regulated expression of cyclin E is necessary for controlled G1 progression (12, 13).Another line of research has addressed changes in the The identity of the G1/S phase kinase responsible for Hi phosphorylation is unknown, although the major late G1 CDK, CDK2, is one attractive candidate. Indeed, Hi is a good substrate for CDK2 phosphorylation in vitro but a poor one for the other G1 CDKs, 4 and 6 (18). CDC2, the major G2 CDK, has been implicated in the phosphorylation of Hi before mitosis (19). These various phosphorylation events have been proposed as necessary steps in providing chromatin access to those proteins...

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Comparative study of the expression of Rb and p53 genes in human colorectal cancers, colon carcinoma cell lines and synchronized human fibroblasts

Cited by 20 publications

References 36 publications

Overexpression of p53 mRNA in colorectal cancer and its relationship to p53 gene mutation

Overexpression of p53 mRNA in colorectal cancer and its relationship to p53 gene mutation

Alteredp16INK4and RB1 Expressions Are Associated with Poor Prognosis in Patients with Nonsmall Cell Lung Cancer

Increased histone H1 phosphorylation and relaxed chromatin structure in Rb-deficient fibroblasts.

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