A role of Miz-1 in Gfi-1-mediated transcriptional repression of CDKN1A.
Zinc-finger (ZF) transcriptional repressor growth factor independence 1 (Gfi-1) has an important role in hematopoiesis and inner ear development, and also functions as an oncoprotein that cooperates with c-Myc in lymphomagenesis. Gfi-1 represses transcription by directly binding to conserved sequences in the promoters of its target genes. CDKN1A encoding p21(Cip1) has been identified as a Gfi-1 target gene and has been shown to contain Gfi-1 binding sites in the upstream promoter region. We show here that Gfi-1 represses CDKN1A in a manner that is independent of its DNA binding activity. Gfi-1 interacts with POZ-ZF transcription factor Miz-1, originally shown to be a c-Myc-interacting partner, and through Miz-1 binds to the CDKN1A core promoter. Interestingly, Gfi-1 and c-Myc, through Miz-1, form a ternary complex on the CDKN1A promoter, and function in collaboration to repress CDKN1A. Gfi-1 knockdown results in enhanced levels of p21(Cip1) and attenuated cell proliferation. Notably, similar to c-Myc, the expression of Gfi-1 is downregulated by transforming growth factor-beta (TGFbeta) and the level of Gfi-1 influences the response of cells to the cytostatic effect of TGFbeta. Our data reveal an important mechanism by which Gfi-1 regulates cell proliferation and may also have implications for understanding the role of Gfi-1 in lymphomagenesis.
Liu
Q
Q
Department of Biological Sciences, University of Toledo, Toledo, OH, USA.
Basu
S
S
Qiu
Y
Y
Tang
F
F
Dong
F
F
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D054697:Cytostatic Agents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008223:Lymphoma / Q000473:pathology; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D016335:Zinc Fingers
D050759:Cyclin-Dependent Kinase Inhibitor p21; D054697:Cytostatic Agents; D004268:DNA-Binding Proteins; C498276:Gfi1 protein, rat; D051741:Kruppel-Like Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D004247:DNA