Identification of transcription factor KLF8 as a downstream target of focal adhesion kinase in its regulation of cyclin D1 and cell cycle progression.
Focal adhesion kinase (FAK) is an important mediator of integrin signaling in the regulation of cell adhesion, migration, survival, and proliferation. Here we report the identification of the transcription factor KLF8 as a target of FAK in cell cycle regulation. KLF8 is induced by FAK and decreased by FAK dominant-negative mutant DeltaC14. Overexpression of KLF8 increases cell cycle progression, whereas inhibition of endogenous KLF8 by siRNA reduces it. Cyclin D1 promoter is identified as a target of KLF8, which is activated both directly by KLF8 binding to the GT box A and by an indirect mechanism through its repression of a potential inhibitory regulator of cyclin D1. Transcription activation of cyclin D1 by FAK requires both Ets family and KLF8 factors in a temporally differential manner. Together, our data provide further insights into molecular mechanism for FAK to regulate cell cycle progression.
Zhao
Jihe
J
Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA.
Bian
Z Christine
ZC
Yee
Kristine
K
Chen
Benjamin P C
BP
Chien
Shu
S
Guan
Jun-Lin
JL
D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001665:Binding Sites; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016023:Integrins / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D000911:Antibodies, Monoclonal; D016023:Integrins; C475812:Klf8 protein, mouse; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; D014157:Transcription Factors; D019938:Cyclin D1; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse