Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through interaction with cyclin D1.
Kruppel-like factor 6 (KLF6) is a tumor suppressor gene inactivated in prostate and colon cancers, as well as in astrocytic gliomas. Here, we establish that KLF6 mediates growth inhibition through an interaction with cyclin D1, leading to reduced phosphorylation of the retinoblastoma protein (Rb) at Ser(795). Furthermore, introduction of KLF6 disrupts cyclin D1-cyclin-dependent kinase (cdk) 4 complexes and forces the redistribution of p21(Cip/Kip) onto cdk2, which promotes G(1) cell cycle arrest. Our data suggest that KLF6 converges with the Rb pathway to inhibit cyclin D1/cdk4 activity, resulting in growth suppression.
Benzeno
Sharon
S
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Narla
Goutham
G
Allina
Jorge
J
Cheng
George Z
GZ
Reeves
Helen L
HL
Banck
Michaela S
MS
Odin
Joseph A
JA
Diehl
J Alan
JA
Germain
Doris
D
Friedman
Scott L
SL
D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis / Q000378:metabolism; D020868:Gene Silencing; D045325:HCT116 Cells; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D019938:Cyclin D1; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases