DIRECT BINDING OF CYCLIN-D TO THE RETINOBLASTOMA GENE-PRODUCT (PRB) AND PRB PHOSPHORYLATION BY THE CYCLIN D-DEPENDENT KINASE CDK4

被引:2
作者
KATO, J
MATSUSHIME, H
HIEBERT, SW
EWEN, ME
SHERR, CJ
机构
[1] ST JUDE CHILDRENS RES HOSP, DEPT TUMOR CELL BIOL, MEMPHIS, TN 38105 USA
[2] HARVARD UNIV, SCH MED, DANA FARBER CANC INST, BOSTON, MA 02115 USA
[3] ST JUDE CHILDRENS RES HOSP, HOWARD HUGHES MED INST, MEMPHIS, TN 38105 USA
关键词
G1; CYCLINS; D-TYPE CYCLINS; CYCLIN-DEPENDENT KINASES (CDKS); RETINOBLASTOMA GENE PRODUCT (PRB);
D O I
暂无
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The product (pRb) of the retinoblastoma gene (RB-1) prevents S-phase entry during the cell cycle, and inactivation of this growth-suppressive function is presumed to result from pRb hyperphosphorylation during late G1 phase. Complexes of the cyclin-dependent kinase, cdk4, and each of three different D-type cyclins, assembled in insect Sf9 cells, phosphorylated a pRb fusion protein in vitro at sites identical to those phosphorylated in human T cells. Only D-type cyclins activated cdk4 enzyme activity, whereas cyclins A, B1, and E did not. When Sf9 cells were coinfected with baculovirus vectors encoding human pRb and murine D-type cyclins, cyclins D2 and D3, but not D1, bound pRb with high stoichiometry in intact cells. Introduction of a vector encoding cdk4, together with those expressing pRb and D-type cyclins, induced pRb hyperphosphorylation and dissociation of cyclins D2 and D3, whereas expression of a kinase-defective cdk4 mutant in lieu of the wild-type catalytic subunit yielded ternary complexes. The transcription factor E2F-1 also bound to pRb in insect cells, and coexpression of cyclin D-cdk4 complexes, but neither subunit alone, triggered pRb phosphorylation and prevented its interaction with E2F-1. The D-type cyclins may play dual roles as cdk4 regulatory subunits and as adaptor proteins that physically target active enzyme complexes to particular substrates.
引用
收藏
页码:331 / 342
页数:12
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