Gene expression and cell cycle arrest mediated by transcription factor DMP1 is antagonized by D-type cyclins through a cyclin-dependent-kinase-independent mechanism

被引:138
作者
Inoue, K
Sherr, CJ
机构
[1] St Jude Childrens Res Hosp, Dept Tumor Cell Biol, Memphis, TN 38105 USA
[2] St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USA
关键词
D O I
10.1128/MCB.18.3.1590
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A novel 761-amino-acid transcription factor, DMP1, contains a central DNA binding domain that includes three imperfect myb repeats flanked by acidic transactivating domains at the amino and carboxyl termini. D-type cyclins associate with a region of the DMP1 DNA binding domain immediately adjacent to the myb repeats to form heteromeric complexes which detectably interact neither with cyclin-dependent kinase 4 (CDK4) nor with DNA, The segment of D-type cyclins required for its interaction with DMP1 falls outside the "cyclin box," which contains the residues predicted to contact CDK4, Hence, D-type cyclin point mutants that do not interact with CDK4 can still bind to DMP1. Enforced coexpression of either of three D-type cyclins (D1, D2, or D3) with DMP1 in mammalian cells canceled its ability to activate gene expression. This property was not shared by cyclins A, B, C, or H; did not depend upon CDK4 or CDK2 coexpression; was not subverted by a mutation in cyclin D1 that prevents its interaction with CDK4; and was unaffected by inhibitors of CDK4 catalytic activity. Introduction of DMP1 into mouse NIH 3T3 fibroblasts inhibited entry into S phase. Cell cycle arrest depended upon the ability of DMP1 to bind to DNA and to transactivate gene expression and was specifically antagonized by coexpression of D-type cyclins, including a D1 point mutant that does not bind to CDK4. Taken together, these findings suggest that DMP1 induces genes that inhibit S phase entry and that D-type cyclins can override DMP1-mediated growth arrest in a CDK-independent manner.
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页码:1590 / 1600
页数:11
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