Activation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1).
Wilks, Deepti P
Huot, Thomas J G
AffiliationCancer Research UK, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK.
MetadataShow full item record
AbstractDeregulation of D-type cyclin-dependent kinases (CDK4 and 6) is widely observed in various human cancers, illustrating their importance in cell cycle control. Like other cyclin-dependent kinases (CDKs), assembly with cyclins is the most critical step for activation of CDK4/6. As previously reported elsewhere, we observed that the level of cyclinD1-CDK4 complex and its associated kinase activity were significantly low in asynchronously proliferating mouse embryo fibroblasts lacking both p21(Cip1) and p27(Kip1) (p21/p27-null MEFs). These evidences imply that p21(Cip1) and p27(Kip1) CDK inhibitors are 'essential activators' of cyclin D-kinases. We, however, discovered here that both the assembly and activation of cyclin D1-CDK4 complex occur when quiescent p21/p27-null MEFs were stimulated to re-enter the cell cycle. This mitogen-induced cyclin D1-kinase activity was blocked by overexpression of p16(INK4a) and resulted in the inhibition of S phase entry in p21/p27-null MEFs. Furthermore, ectopic expression of p34(SEI-1), a mitogen-induced CDK4 binding protein, increased the levels of active cyclinD1-CDK4 complex in asynchronously proliferating p21/p27-null MEFs. Together, our results suggest that there are several independent ways to stimulate the assembly of cyclin D1-CDK4 kinases. Although p21(Cip1) and p27(Kip1) play a role in this process, our results demonstrate that additional mechanisms must occur in G0 to S phase transition.
CitationActivation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1). 2002, 21 (53):8067-74 Oncogene
- P27Kip1 and p21Cip1 are not required for the formation of active D cyclin-cdk4 complexes.
- Authors: Bagui TK, Mohapatra S, Haura E, Pledger WJ
- Issue date: 2003 Oct
- Cell cycle exit during terminal erythroid differentiation is associated with accumulation of p27(Kip1) and inactivation of cdk2 kinase.
- Authors: Hsieh FF, Barnett LA, Green WF, Freedman K, Matushansky I, Skoultchi AI, Kelley LL
- Issue date: 2000 Oct 15
- Analysis of cyclin D3-cdk4 complexes in fibroblasts expressing and lacking p27(kip1) and p21(cip1).
- Authors: Bagui TK, Jackson RJ, Agrawal D, Pledger WJ
- Issue date: 2000 Dec
- Multifaceted regulation of cell cycle progression by estrogen: regulation of Cdk inhibitors and Cdc25A independent of cyclin D1-Cdk4 function.
- Authors: Foster JS, Henley DC, Bukovsky A, Seth P, Wimalasena J
- Issue date: 2001 Feb
- BCL-x(L) and BCL2 delay Myc-induced cell cycle entry through elevation of p27 and inhibition of G1 cyclin-dependent kinases.
- Authors: Greider C, Chattopadhyay A, Parkhurst C, Yang E
- Issue date: 2002 Nov 7