p53 regulates Cdc2 independently of inhibitory phosphorylation to reinforce radiation-induced G2 arrest in human cells

Winters, ZE; Ongkeko, Weg M.; Harris, Adrian L.; Norbury, Chris J.

doi:10.1038/sj.onc.1201991

Cited by 65 publications

(65 citation statements)

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“…It was further determined that KLF4 transactivates the p21 promoter by binding to a specific Sp-1-like cis-element in the proximal region of the promoter (Zhang et al, 2000). Activation of p21 expression following DNA damage causes cell-cycle arrest at both the G1-S and G2-M transition points (Bissonnette and Hunting, 1998;Winters et al, 1998). In addition to its effects on p21 expression, KLF4 has been reported to inhibit expression of cyclin D1 and cyclin B, which promote progression through the G1-S and G2-M boundaries, respectively (Shie et al, 1999Yoon and Yang, 2004).…”

Section: Introductionmentioning

confidence: 99%

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

et al. 2009

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Kruppel-like factor 4 (KLF4) is a transcription factor that participates in both tumor suppression and oncogenesis. To determine the association of KLF4 with tumorigenesis, we integrated data assembled in the Oncomine database and discovered a decrease in KLF4 gene transcripts in breast cancers. Further analysis of the database also showed a correlation between KLF4 expression and estrogen receptor-a (ERa) positivity. Knockdown of KLF4 in MCF-7 cells elevated the growth rate of these cells in the presence of estrogen. Therefore, we examined the interaction between KLF4 and ERa, and found that KLF4 bound to the DNA-binding region of ERa. KLF4 thus inhibits the binding of ERa to estrogen response elements in promoter regions, resulting in a reduction in ERa target gene transcription. Earlier studies have reported that KLF4 is transcriptionally activated by p53 following DNA damage. We also showed that activation of p53 decreased the transcriptional activity of ERa by elevating KLF4 expression. Our studies discovered a novel molecular network between p53, KLF4 and ERa. As both p53 and ERa are involved in cell growth and apoptosis, these results may explain why KLF4 possesses both tumor suppressive and oncogenic functions in breast cancers.

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Section: Introductionmentioning

confidence: 99%

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

et al. 2009

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“…Despite accumulating evidence suggesting that p21 could regulate DNA damage-induced G2 arrest (Bunz et al, 1998;Dulic et al, 1998;Winters et al, 1998;Chan et al, 2000;Flatt et al, 2000;Baus et al, 2003), it is widely assumed that this inhibitor does not play a direct role in inactivating mitotic cyclin-Cdk1 complexes, partly because of its low affinity toward Cdk1 (Harper et al, 1995). Indeed, p21 has been detected only in a minority of cyclin B1-Cdk1 complexes after DNA damage (Levedakou et al, 1995;Barboule et al, 1999;Flatt et al, 2000) or even after overexpression of p53 or p21 (Winters et al, 1998;Smits et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, p21 has been detected only in a minority of cyclin B1-Cdk1 complexes after DNA damage (Levedakou et al, 1995;Barboule et al, 1999;Flatt et al, 2000) or even after overexpression of p53 or p21 (Winters et al, 1998;Smits et al, 2000). This is in striking contrast to another mitotic regulator, cyclin A-Cdk1, which massively associates with p21 in response to DNA damage, suggesting that, at least in normal human fibroblasts (NHFs), Cdk1 could be a major target of this inhibitor (Dulic et al, 1998;Baus et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, p21 has been detected only in a minority of cyclin B1-Cdk1 complexes after DNA damage (Levedakou et al, 1995;Barboule et al, 1999;Flatt et al, 2000) or even after overexpression of p53 or p21 (Winters et al, 1998;Smits et al, 2000). This is in striking contrast to another mitotic regulator, cyclin A-Cdk1, which , a drug that specifically provokes G2 arrest.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, the maintenance of G2 arrest is highly p53 dependent and involves at least two of its transcriptional targets, the Cdk inhibitor p21 Waf1/ Cip1 (p21) and the adaptor protein 14-3-3 (for reviews, see Ohi and Gould, 1999;Taylor and Stark, 2001). The latter protein has been proposed to mediate nuclear exclusion of cyclin B1-Cdk1, an event thought to be necessary for blocking mitosis (Chan et al, 1999;van Hemert et al, 2001).Despite accumulating evidence suggesting that p21 could regulate DNA damage-induced G2 arrest (Bunz et al, 1998;Dulic et al, 1998;Winters et al, 1998;Chan et al, 2000;Flatt et al, 2000;Baus et al, 2003), it is widely assumed that this inhibitor does not play a direct role in inactivating mitotic cyclin-Cdk1 complexes, partly because of its low affinity toward Cdk1 (Harper et al, 1995). Indeed, p21 has been detected only in a minority of cyclin B1-Cdk1 complexes after DNA damage (Levedakou et al, 1995;Barboule et al, 1999;Flatt et al, 2000) or even after overexpression of p53 or p21 (Winters et al, 1998;Smits et al, 2000).…”

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p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress

Charrier‐Savournin

Château

Gire

et al. 2004

MBoC

179

137

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G2 arrest of cells suffering DNA damage in S phase is crucial to avoid their entry into mitosis, with the concomitant risks of oncogenic transformation. According to the current model, signals elicited by DNA damage prevent mitosis by inhibiting both activation and nuclear import of cyclin B1-Cdk1, a master mitotic regulator. We now show that normal human fibroblasts use additional mechanisms to block activation of cyclin B1-Cdk1. In these cells, exposure to nonrepairable DNA damage leads to nuclear accumulation of inactive cyclin B1-Cdk1 complexes. This nuclear retention, which strictly depends on association with endogenous p21, prevents activation of cyclin B1-Cdk1 by Cdc25 and Cdk-activating kinase as well as its recruitment to the centrosome. In p21-deficient normal human fibroblasts and immortal cell lines, cyclin B1 fails to accumulate in the nucleus and could be readily detected at the centrosome in response to DNA damage. Therefore, in normal cells, p21 exerts a dual role in mediating DNA damage-induced cell cycle arrest and exit before mitosis. In addition to blocking pRb phosphorylation, p21 directly prevents mitosis by inactivating and maintaining the inactive state of mitotic cyclin-Cdk complexes. This, with subsequent degradation of mitotic cyclins, further contributes to the establishment of a permanent G2 arrest. INTRODUCTIONCyclin B1-Cdk1 is a master mitotic regulator and is therefore an ultimate target toward which most, if not all, antiproliferative signals generated during S and G2 phase converge. In cycling cells, cyclin B1 synthesis increases during late S-early G2 phase (Pines and Hunter, 1989), but the newly formed cyclin B1-Cdk1 complexes are kept inactive by inhibitory phosphorylations on Thr 14 and Tyr 15 (Norbury et al., 1991) and by active and constant nuclear exclusion via Crm1-mediated nuclear export (Hagting et al., 1998;Yang et al., 1998). The rapid nuclear accumulation of cyclin B1-Cdk1 that occurs in prophase coincides with phosphorylation of cyclin B1 at the cytoplasmic retention sequence, which also contains its nuclear export sequence (Hagting et al., 1999; for review, see Porter and Donoghue, 2003). Nuclear import of cyclin B1-Cdk1 coincides with Cdc25 phosphatase-mediated dephosphorylation of Thr 14 and Tyr 15 on Cdk1 (Berry and Gould, 1996). Based on these observations, it has been assumed that cytoplasmic cyclin B1-Cdk1 is not active. However, both earlier and most recent work suggest that cyclin B1-Cdk1 might already be activated in the cytoplasm and most probably at the centrosome (Heald et al., 1993;De Souza et al., 2000;Hirota et al., 2003;Jackman et al., 2003).According to the current model, signals elicited by DNA damage in S and G2 phases prevent mitotic entry by inhibiting both activation (via inactivation of Cdc25) and nuclear import of cyclin B1-Cdk1 (Jin et al., 1998;Yang et al., 1998Yang et al., , 2001Deming et al., 2001). G2 arrest is initiated via phosphorylation of Cdc25 by Chk1/2 kinases, a process that does not require active p53. On the other hand, the...

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DNA damage uncouples the mitogenic response to IGF‐I in MCF‐7 malignant breast cancer cells by switching the roles of PI3 kinase and p21^WAF1/Cip1

Clark

Perks

Winters

et al. 2005

Intl Journal of Cancer

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In addition to its mitogenic and survival actions, recent evidence indicates that IGF-I can enhance DNA repair, implying IGF activity may limit the efficacy of many therapeutic strategies that rely on induction of DNA damage. Although the individual pathways by which DNA damage and IGF-I act are well understood, the cross-talk between these signaling events is not well defined. We examined the effects of DNA damage on the IGF-I response of MCF-7 breast cancer cells. Cells were exposed to the UV mimetic, 4-NQO, or the c-irradiation mimetic and chemotherapeutic drug, bleomycin; cellular proliferation was assessed by cell counting, tritiated thymidine incorporation and FACS cell cycle analysis. Although IGF-I acutely suppressed the p53 response to both agents, it subsequently enhanced the chronic increase in p53 and p21 WAF1/Cip1 , resulting in cell cycle arrest; however, no apoptosis was observed. Use of specific inhibitors demonstrated that PI3 kinase was utilized with p38 MAPK to induce the p53 response to DNA damage, but was also utilized by IGF-I to diminish the acute p53 response. In addition, p21 WAF1/Cip1 was increased by IGF-I, which has previously been shown to contribute to the mitogenic response. Here we demonstrate that with DNA damage IGF-I can also enhance the chronic p53-dependent increase in p21 WAF1/Cip1 , culminating in growth arrest. Overall, we have shown that PI3 kinase and p21 WAF1/Cip1 play dual roles in mediating the mitogenic response to IGF-I, but these are both switched by cellular DNA damage to mediate a growth arrest. ' 2005 Wiley-Liss, Inc.

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p53 regulates Cdc2 independently of inhibitory phosphorylation to reinforce radiation-induced G2 arrest in human cells

Cited by 65 publications

References 40 publications

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress

DNA damage uncouples the mitogenic response to IGF‐I in MCF‐7 malignant breast cancer cells by switching the roles of PI3 kinase and p21^WAF1/Cip1

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p53 regulates Cdc2 independently of inhibitory phosphorylation to reinforce radiation-induced G2 arrest in human cells

Cited by 65 publications

References 40 publications

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress

DNA damage uncouples the mitogenic response to IGF‐I in MCF‐7 malignant breast cancer cells by switching the roles of PI3 kinase and p21WAF1/Cip1

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DNA damage uncouples the mitogenic response to IGF‐I in MCF‐7 malignant breast cancer cells by switching the roles of PI3 kinase and p21^WAF1/Cip1