Reciprocal Regulation via Protein-Protein Interaction between c-Myc and p21   in DNA Replication and Transcription

Kitaura, Hirotake; Shinshi, Minako; Uchikoshi, Yasuko; Ono, Takashi; Tsurimoto, Toshiki; Yoshikawa, Hiroshi; Iguchi‐Ariga, Sanae M.M.; Ariga, Hiroyoshi

doi:10.1074/jbc.275.14.10477

Cited by 124 publications

(86 citation statements)

References 48 publications

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“…Moreover, it was shown that p21 can bind to N-terminus of c-Myc, interfere with c-Myc-Max association and suppress cMyc-dependent transcription. 43 At the same time, c-Myc binds to C-terminus of p21, in competition with PCNA and thus counteracts p21-dependent inhibition of DNA synthesis. The balance of the reciprocal inactivation between c-Myc and p21 may determine the course of cellular processes such as cell proliferation, differentiation and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…The balance of the reciprocal inactivation between c-Myc and p21 may determine the course of cellular processes such as cell proliferation, differentiation and apoptosis. 43 Accordingly, Frederick et al 44 showed that suppression of c-Myc using antisense oligonucleotides, in the absence of p53, was sufficient to trigger apoptosis in Tu-138 cells. Thus, inactivation of c-Myc-Max association by p21 could be one of the possible mechanisms of its proapoptotic activity in the absence of functional p53, which was the case in our study.…”

Section: Discussionmentioning

confidence: 99%

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Endogenous p21WAF1/CIP1 status predicts the response of human tumor cells to wild-type p53 and p21WAF1/CIP1 overexpression

et al. 2003

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Expression of exogenous wild-type (wt) p53 protein can suppress the growth and/or induce apoptosis in different tumor cells. The effect of exogenous p21 WAF1/CIP1 expression is more controversial: while it can induce apoptosis in some cells, it can protect against p53-mediated apoptosis in others. We used adenoviral vectors to introduce p53 and p21 WAF1/CIP1 genes into human tumor cell lines with different p53 and/or p21 WAF1/CIP1 status. The cell growth inhibition and the induction of apoptosis were measured. Overexpression of wt p53 induced more efficient growth inhibition and apoptosis in SW 620 (mutant p53) and HeLa (inactivated p53 protein) than in MCF-7 (wt p53) and CaCo-2 cell line, which was the most resistant to p53 overexpression despite the p53 mutation. Unlike HeLa and SW 620 cells, the basal p21 protein level was readily detected in CaCo-2 and MCF-7 cells. Overexpression of p21 WAF1/CIP1 gene induced somewhat less pronounced growth inhibition of all cell lines tested, but it also induced apoptosis in HeLa and SW 620 cells. These results suggest that the basal, but not the inducible, levels of p21 WAF1/CIP1 protein in tumor cells could protect from p53-mediated apoptosis. On the other hand, overexpression of p21 WAF1/CIP1 gene itself can induce apoptosis in cells with no basal p21 WAF1/CIP1 protein level. Possible mechanisms of the differential response to these genes are discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Endogenous p21WAF1/CIP1 status predicts the response of human tumor cells to wild-type p53 and p21WAF1/CIP1 overexpression

et al. 2003

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“…However, in MCF10A cells, UCN-01 failed to induce reaccumulation of Cdc25A suggesting that the transactivation function of p53 may also regulate Cdc25A. It is known that transcription of Cdc25A can be regulated by both c-Myc and E2F, both of which can in turn be suppressed by p21 WAF1 (Vigo et al, 1999;Kitaura et al, 2000;Santoni-rugiu et al, 2000). Therefore, in addition to inhibiting Cdk2 activity, p21 WAF1 may also prevent S phase progression by downregulating Cdc25A transcription.…”

Section: Discussionmentioning

confidence: 99%

Distinct roles for p53 transactivation and repression in preventing UCN-01-mediated abrogation of DNA damage-induced arrest at S and G2 cell cycle checkpoints

et al. 2005

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The topoisomerase I inhibitor SN38 arrests cell cycle progression primarily in S or G 2 phases of the cell cycle in a p53-independent manner. The Chk1 inhibitor, 7-hydroxystaurosporine (UCN-01), overcomes both S and G 2 arrest preferentially in cells mutated for p53, driving cells through a lethal mitosis and thereby enhancing cytotoxicity. The mechanism by which p53 maintains S and G 2 arrest was investigated here. The p53 wild-type MCF10A cells were arrested in S phase by incubation with SN38 for 24 h. Subsequent incubation with UCN-01 failed to abrogate arrest. To examine the impact of p53, MCF10A cells were developed, which express the tetramerization domain of p53 to inhibit endogenous p53 function. These cells were attenuated in SN38-mediated induction of p21 WAF1 , and UCN-01 induced S, but not G 2 progression. In contrast, MCF10A cells expressing short hairpin RNA to ablate p53 expression underwent both S and G 2 phase progression with UCN-01. The difference in G 2 progression was attributed to p53-mediated gene repression; the MCF10A cells expressing the tetramerization domain retained p53 protein and repressed both cyclin B and Chk1, while cells ablated for p53 did not repress these proteins. Hence, inhibition of p53 activator function permits S phase abrogation, while additional inhibition of p53 repressor function is required for abrogation of G 2 arrest. These studies provide a mechanistic explanation for how this therapeutic strategy can selectively target tumor cells.

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“…Glutathione S-transferase (GST) fusion p21 wild type and deletions cloned in pGEX-6P-1 were kind gifts from Dr. Hiroyoshi Ariga. 29 Monoclonal antibodies against p125 (78F5), p50 (13D5 and 17D2), and rabbit polyclonal antibodies against p68, p12 were used as previously described. 20 Rabbit polyclonal antibody against p50 was generated by using full length p50 over expressed in E. coli as antigen.…”

Section: Methodsmentioning

confidence: 99%

Direct Interaction of p21 with p50, the Small Subunit of Human DNA Polymerase Delta

Xie²,

Rahmeh³

et al. 2006

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=2425 KEY WORDS ReportDirect Interaction of p21 with p50, the Small Subunit of Human DNA Polymerase Delta ABSTRACT Using a yeast two-hybrid screening technique and the p50 subunit of human DNA polymerase delta (pol δ) as a bait, p21 was found to interact with the p50 subunit of pol δ. A direct interaction between p21 and p50 was confirmed by using ELISA and pull-down assays with purified proteins. The interaction sites between p50 and p21 were mapped by pull down assays with GST deletion mutants. Residues 127-193 constitute the primary interaction region on p50 to which p21 binds, while p50 binds to the C-terminal 26 residues of p21. A histone kinase activity was associated with the highly purified calf thymus pol δ and addition of purified recombinant p21 inhibited the kinase activity in a dose dependent manner. p50 is phosphorylated in vivo and can be phosphorylated by CDK2/cyclinA in vitro. In vivo evidence of p21 association with p50 was obtained by coimmunoprecipitation using MCF7 cells. It was also shown that the association of p21 with p50 and other components of the pol δ complex increased in MCF7 cells treated with adriamycin. Our results suggested that p50 might target or anchor p21 to pol δ complex upon certain DNA damage such as adriamycin treatment.

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Reciprocal Regulation via Protein-Protein Interaction between c-Myc and p21 in DNA Replication and Transcription

Cited by 124 publications

References 48 publications

Endogenous p21WAF1/CIP1 status predicts the response of human tumor cells to wild-type p53 and p21WAF1/CIP1 overexpression

Endogenous p21WAF1/CIP1 status predicts the response of human tumor cells to wild-type p53 and p21WAF1/CIP1 overexpression

Distinct roles for p53 transactivation and repression in preventing UCN-01-mediated abrogation of DNA damage-induced arrest at S and G2 cell cycle checkpoints

Direct Interaction of p21 with p50, the Small Subunit of Human DNA Polymerase Delta

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