Role of the retinoblastoma protein family, pRB, p107 and p130 in the negative control of cell growth

Graña, Xavier; Garriga, Judit; Mayol, Xavier

doi:10.1038/sj.onc.1202575

Cited by 308 publications

(310 citation statements)

References 131 publications

(223 reference statements)

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“…In the non-irradiated proliferating REF and E1A+cHa-ras cells, pocket proteins pRb, p107, and p130 were detected in both phosphorylated and non-phosphorylated forms ( Figure 3a). However, the amounts of these proteins were signi®cantly higher in E1A+cHa-ras transformants as compared with normal REF cells (Grana et al, 1998) (Figure 3b, marked A and B), the process being correlated with a decrease in the proportion of S phase cells. Remarkably, E1A+cHa-ras transformants did not reveal any signi®cant changes in the ratio of phosphorylated/non-phosphorylated forms in irradiated cells (Figure 3a).…”

Section: Resultsmentioning

confidence: 94%

Deregulation of p53/p21Cip1/Waf1 pathway contributes to polyploidy and apoptosis of E1A+cHa-ras transformed cells after γ-irradiation

et al. 1999

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The p53/p21 Cip1/Waf1 -dependent checkpoint control of G1/S and G2/M phases of the cell cycle in response to DNA damage is an important mechanism of genome stability maintenance in normal cells. In many tumor cells, due to frequent point mutations and deletions of p53, the stringent control of the cell cycle and apoptosis is compromised. We have examined the cell cycle control and cell death of the rat embryo ®broblast cells (REF) transformed by E1A+cHa-ras oncogenes and expressing wild type p53. Gamma-irradiation at a dosage of 6 Gy has been used to analyse the p53-dependent transactivation of the target p21 cip1/waf1 gene and the levels of activity of cyclin-dependent kinases. Our results show that the cell cycle inhibitors p21 Cip1/Waf1 and p27 KIP accumulate in response to irradiation both in REF and E1A+cHa-ras cells. In contrast to normal REF cells, the accumulation of p21 Cip1/Waf1 and p27 KIP inhibitors, however, does not lead to inhibition of Cdk2 and cyclins E, A-associated kinase activities and to a G1/S block in E1A+cHa-ras cells. It is unlikely that the lack of inhibitory function of p21 Cip1/Waf1 can be explained by its inability to bind Cdk2 and Cdk4 kinases or PCNA. Moreover, the p21 Cip1/Waf1 -associated kinase activity is increased upon g-irradiation of E1A+cHa-ras cells. We suggest that inactivation of p21 Cip1/Waf1 may be accounted for by its interaction with E1A oncoproducts as the inhibitor is detected in immunoprecipitates using E1A-speci®c antibodies. During a temporary G2/M delay induced by g-irradiation, E1A+cHa-ras transformants continue DNA replication, which leads to accumulation of polyploid cells with lobulated nuclei and micronuclei. Thus, DNA damage of E1A+cHa-ras transformed cells, with a combination of functionally active wild type p53 and inactive p21 Cip1/Waf1 , contributes to formation of polyploid cells which then die due to apoptosis.

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Section: Resultsmentioning

confidence: 94%

Deregulation of p53/p21Cip1/Waf1 pathway contributes to polyploidy and apoptosis of E1A+cHa-ras transformed cells after γ-irradiation

et al. 1999

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“…We next determined whether the observed changes in pocket protein phosphorylation were associated with changes in pocket protein-E2F complexes typical of growth-arrested cells (reviewed in Grañ a et al 31 ). To this end, we performed E2F-4 immunoprecipitation and tested immunocomplexes for the presence of each pocket protein.…”

Section: Changes In E2f/pocket Protein Complexes and E2f-dependent Trmentioning

confidence: 99%

The fate of pancreatic tumor cell lines following p16 overexpression depends on the modulation of CDK2 activity

et al. 2004

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Restitution of lost tumor-suppressor activities may be a promising strategy to target specifically cancer cells. However, the action of ectopically expressed tumor-suppressor genes depends on genetic background of tumoral cells. Ectopic expression of p16 INK4a induces either cell cycle arrest or apoptosis in different pancreatic cancer cell lines. We examined the molecular mechanisms mediating these two different cellular responses to p16 overexpression. Ectopic expression of p16 leads to G1 arrest in NP-9 cells by redistributing p21/p27 CKIs and inhibiting cyclin-dependent kinase CDK2 activity. In contrast, in NP-18 cells cyclin E (CycE)/ CDK2 activity is significantly higher and is not downregulated by p16-mediated redistribution of p21/p27. Moreover, inhibition of CDK4 activity with fascaplysine, which does not affect CycE/ CDK2 activity, reduces pocket protein phosphorylation in both cell lines, but fails to induce growth arrest. Like overexpression of p16, fascaplysine induces apoptosis in NP-18 cells, suggesting that inhibition of D-type cyclin/CDK activity in cells with high levels of CycE/CDK2 activity activates an apoptotic pathway. Inhibition of CycE/CDK2 activity via ectopic expression of p21 in NP-18 cells overexpressing p16 induces growth arrest and prevents p16-mediated apoptosis. Accordingly, silencing of p21 expression by using small interfering RNA switches the fate of p16-expressing NP-9 cells from cell cycle arrest to apoptosis. Our data suggest that, after CDK4/6 inactivation, the fate of pancreatic tumor cells depends on the ability to modulate CDK2 activity.

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“…The retinoblastoma gene product pRB is a nuclear phosphoprotein that plays a pivotal role in the decision process of a cell to enter or exit the cell cycle (Weinberg, 1995;Grana et al, 1998). pRB is present throughout the cell cycle, but its phosphorylation state changes in a cell cycle-dependent manner.…”

Section: Prb and Growth Controlmentioning

confidence: 99%

Developmental defects and tumor predisposition in Rb mutant mice

Vooijs

Berns

1999

Oncogene

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Role of the retinoblastoma protein family, pRB, p107 and p130 in the negative control of cell growth

Cited by 308 publications

References 131 publications

Deregulation of p53/p21Cip1/Waf1 pathway contributes to polyploidy and apoptosis of E1A+cHa-ras transformed cells after γ-irradiation

Deregulation of p53/p21Cip1/Waf1 pathway contributes to polyploidy and apoptosis of E1A+cHa-ras transformed cells after γ-irradiation

The fate of pancreatic tumor cell lines following p16 overexpression depends on the modulation of CDK2 activity

Developmental defects and tumor predisposition in Rb mutant mice

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