The Cyclin-dependent Kinase Inhibitor p21WAF1/Cip1 Is an Antiestrogen-regulated Inhibitor of Cdk4 in Human Breast Cancer Cells

Skildum, Andrew; Mukherjee, Shibani; Conrad, Susan E.

doi:10.1074/jbc.m109179200

Cited by 32 publications

(33 citation statements)

References 41 publications

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“…cells and that promoting the formation of p21-free CDK complexes is sufficient for CDK activation and cell cycle progression (16,17,51,53). Together, these results suggest that a key mechanism by which c-Myc promotes proliferation of breast cancer cells in the presence of ICI is by decreasing p21 levels.…”

Section: P21 Is Targeted In Myc-induced Proliferation Of Mcf-7 Cellssupporting

confidence: 53%

“…Our results with stable MCF-7 derivatives indicated that c-Myc can repress p21 expression but did not directly address whether the previously reported (18,22,51) decreases in p21 in response to E2 treatment are mediated via c-Myc. We therefore used RNA interference to demonstrate that c-Myc expression is required for the E2-mediated decrease in p21 in MCF-7 cells and thus identified c-Myc as the first direct link between E2 and p21 in breast cancer cells.…”

Section: P21 Is Targeted In Myc-induced Proliferation Of Mcf-7 Cellsmentioning

confidence: 66%

“…Decreasing p21 expression using antisense oligonucleotides is sufficient to induce cell cycle progression in ICI-treated cells (22), whereas induction of cyclin A using the AP-inducible system is not. 2 In addition, previous work has demonstrated that p21 is a critical regulator of CDK activity in human breast cancer cells and that promoting the formation of p21 free CDK complexes is sufficient for CDK activation and cell cycle progression (16,17,51,53). This suggests that a key mechanism by which c-Myc promotes proliferation of breast cancer cells in the presence of ICI is by decreasing p21 levels.…”

Section: P21 Is Targeted In Myc-induced Proliferation Of Mcf-7 Cellsmentioning

confidence: 92%

“…One difference between the two studies is that the earlier report focused on early events (6 -16 h) following transfection with c-Myc antisense, whereas we studied cells at 48 h after transfection with c-Myc siRNA. We chose this time point because our previous work and the work of others have shown that, upon ICI treatment, p21 accumulates over 48 h, leading to CDK inhibition and complete cell cycle arrest (51,53).…”

Section: P21 Is Targeted In Myc-induced Proliferation Of Mcf-7 Cellsmentioning

confidence: 99%

See 3 more Smart Citations

c-Myc Suppresses p21WAF1/CIP1 Expression during Estrogen Signaling and Antiestrogen Resistance in Human Breast Cancer Cells

Mukherjee

Conrad

2005

Journal of Biological Chemistry

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101

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Section: P21 Is Targeted In Myc-induced Proliferation Of Mcf-7 Cellssupporting

confidence: 53%

Section: P21 Is Targeted In Myc-induced Proliferation Of Mcf-7 Cellsmentioning

confidence: 66%

Section: P21 Is Targeted In Myc-induced Proliferation Of Mcf-7 Cellsmentioning

confidence: 92%

Section: P21 Is Targeted In Myc-induced Proliferation Of Mcf-7 Cellsmentioning

confidence: 99%

See 2 more Smart Citations

c-Myc Suppresses p21WAF1/CIP1 Expression during Estrogen Signaling and Antiestrogen Resistance in Human Breast Cancer Cells

Mukherjee

Conrad

2005

Journal of Biological Chemistry

Self Cite

101

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“…Modulation of p21 functions depends on its final concentration in cells; lower levels of p21 initially promote cell cycle progression by stimulation of cyclin-CDK assembly (52,53), whereas higher levels will inhibit cyclin-CDK activity. Our data suggest that only when there are no p21-free cyclin A-CDK2 complexes will p21 interact with PCNA.…”

Section: P21 Down-regulation Is Required For Replication Restartmentioning

confidence: 99%

Decreased p21 Levels Are Required for Efficient Restart of DNA Synthesis after S Phase Block

Gottifredi

McKinney

Poyurovsky

et al. 2004

Journal of Biological Chemistry

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The cyclin-dependent kinase inhibitor p21, a major transcriptional target of the tumor suppressor p53, plays a critical role in cell cycle arrest in G 1 and G 2 after DNA damage. It was previously shown that in some human cell lines when S phase is arrested, p53 is transcriptionally impaired such that some p53 targets including p21 are only weakly induced. We show here that during S phase arrest proteasome-mediated turnover of p21 is significantly increased in a manner that is independent of p53. It is well established that p21 can interact both with cyclin-dependent kinase complexes and with proliferating cell nuclear antigen (PCNA). Interestingly, the scant amount of p21 detected during S phase block cannot fully saturate cyclin A-cyclin-dependent kinase 2 complexes and does not interact detectably with PCNA. Importantly, DNA elongation assays in isolated nuclei show that the C terminus of p21 containing the PCNAbinding domain effectively blocks this process. This implies that p21 down-regulation could be an essential requirement for efficient restart of DNA synthesis. In line with this, only cells expressing low levels of p21 immediately progress through the cell cycle upon release from S phase arrest, whereas the remaining few high p21 producing cells move much more slowly through S. Thus, p21 down-regulation is multiply determined and is required for the reversibility of the arrest in S phase.Stress signals arising from various pathways such as DNA strand breaks, stalled DNA replication forks, ribonucleotide deprivation, and hypoxia (1-3) all appear to converge on the activation of p53 leading to transcriptional activation of p53 target genes such as the cyclin-dependent kinase inhibitor p21Cip1/Waf1 (hereafter referred to as p21). Transcriptional targets of p53 play crucial roles in both G 1 and G 2 checkpoints. Generally, when p53 is stabilized cells arrest irreversibly in G 1 and/or G 2 but not in S phase. Compounds such as hydroxyurea (HU), 1 which inhibits the activity of ribonucleotide reductase (4); aphidicolin (APH), which blocks DNA polymerase ␣ (5); and hypoxia (6) cause a reversible late G 1 /early S phase arrest independent of p53. Interestingly, however, although p53 protein levels are increased as a consequence of these treatments, it is at least partially held in check because transcriptional targets such as p21 do not accumulate (7-9).The p21 Cip1/waf1 protein, a member of a family of cyclin-dependent kinase (CDK) inhibitors, controls the G 1 /S transition through its ability to bind tightly to cyclinD-CDK4, cyclinE-CDK2, and cyclin A-CDK2 complexes (10). p21 also binds to the replicative clamp protein PCNA and interferes with its interactions with replication factor C (11, 12), DNA polymerase ␦ (13), and FEN1 (14), thereby inhibiting DNA replication in vitro (15-17). Far higher concentrations of p21 are required to inhibit PCNA activities in DNA repair than to repress DNA replication in vitro (15,18,19).Although much information is available about the activities of p21, the mechanisms gover...

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Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells

Donadelli

Costamagna

Faggioli

et al. 2003

Molecular Carcinogenesis

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In cells with an altered p53 gene, the expression of p21(WAF1/CIP1), a potent inhibitor of cyclin-dependent kinases, can be induced by histone deacetylase (HDAC) inhibitors via a p53-independent pathway, which may play a critical role in arrest of cell growth. Accordingly, HDAC inhibitors such as trichostatin A (TSA) have potential utility in pancreatic cancer, as most of these tumors possess mutations in p53, which in fact is the main cause of chemoresistance to 5-fluorouracil. We have analyzed the effect of TSA on the proliferation of nine pancreatic adenocarcinoma cell lines, all containing a mutated p53 gene. TSA strongly inhibited the cellular growth of all these cell lines at submicromolar concentrations. The cellular mechanisms underlying this effect consisted of cell cycle arrest at the G2 phase and apoptotic cell death. The expression of p21(WAF1/CIP1) normally induced at the transcriptional level by p53 was also strongly activated by TSA. These findings suggest that inhibitors of HDAC may represent a novel therapeutic strategy for treatment of pancreatic cancer.

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The Cyclin-dependent Kinase Inhibitor p21WAF1/Cip1 Is an Antiestrogen-regulated Inhibitor of Cdk4 in Human Breast Cancer Cells

Cited by 32 publications

References 41 publications

c-Myc Suppresses p21WAF1/CIP1 Expression during Estrogen Signaling and Antiestrogen Resistance in Human Breast Cancer Cells

c-Myc Suppresses p21WAF1/CIP1 Expression during Estrogen Signaling and Antiestrogen Resistance in Human Breast Cancer Cells

Decreased p21 Levels Are Required for Efficient Restart of DNA Synthesis after S Phase Block

Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells

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