Activation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1).

2.50
Hdl Handle:
http://hdl.handle.net/10541/84057
Title:
Activation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1).
Authors:
Sugimoto, Masataka; Martin, Nicholas; Wilks, Deepti P; Tamai, Katsuyuki; Huot, Thomas J G; Pantoja, Cristina; Okumura, Ko; Serrano, Manuel; Hara, Eiji
Abstract:
Deregulation 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.
Affiliation:
Cancer Research UK, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK.
Citation:
Activation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1). 2002, 21 (53):8067-74 Oncogene
Journal:
Oncogene
Issue Date:
21-Nov-2002
URI:
http://hdl.handle.net/10541/84057
DOI:
10.1038/sj.onc.1206019
PubMed ID:
12444543
Type:
Article
Language:
en
ISSN:
0950-9232
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorSugimoto, Masatakaen
dc.contributor.authorMartin, Nicholasen
dc.contributor.authorWilks, Deepti Pen
dc.contributor.authorTamai, Katsuyukien
dc.contributor.authorHuot, Thomas J Gen
dc.contributor.authorPantoja, Cristinaen
dc.contributor.authorOkumura, Koen
dc.contributor.authorSerrano, Manuelen
dc.contributor.authorHara, Eijien
dc.date.accessioned2009-10-12T12:09:28Z-
dc.date.available2009-10-12T12:09:28Z-
dc.date.issued2002-11-21-
dc.identifier.citationActivation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1). 2002, 21 (53):8067-74 Oncogeneen
dc.identifier.issn0950-9232-
dc.identifier.pmid12444543-
dc.identifier.doi10.1038/sj.onc.1206019-
dc.identifier.urihttp://hdl.handle.net/10541/84057-
dc.description.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.en
dc.language.isoenen
dc.subjectFoetal Blooden
dc.subjectTumour Suppressor Proteinsen
dc.subject.meshAnimals-
dc.subject.meshCattle-
dc.subject.meshCell Cycle-
dc.subject.meshCell Cycle Proteins-
dc.subject.meshContact Inhibition-
dc.subject.meshCulture Media-
dc.subject.meshCulture Media, Serum-Free-
dc.subject.meshCyclin-Dependent Kinase 4-
dc.subject.meshCyclin-Dependent Kinase Inhibitor p21-
dc.subject.meshCyclin-Dependent Kinase Inhibitor p27-
dc.subject.meshCyclin-Dependent Kinases-
dc.subject.meshCyclins-
dc.subject.meshEmbryo, Mammalian-
dc.subject.meshEnzyme Activation-
dc.subject.meshFetal Blood-
dc.subject.meshFibroblasts-
dc.subject.meshG0 Phase-
dc.subject.meshGene Targeting-
dc.subject.meshGrowth Substances-
dc.subject.meshHumans-
dc.subject.meshMacromolecular Substances-
dc.subject.meshMice-
dc.subject.meshMitogens-
dc.subject.meshNuclear Proteins-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshS Phase-
dc.subject.meshTrans-Activators-
dc.subject.meshTumor Suppressor Proteins-
dc.titleActivation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1).en
dc.typeArticleen
dc.contributor.departmentCancer Research UK, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK.en
dc.identifier.journalOncogeneen

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