Gfi-1 represses CDKN2B encoding p15INK4B through interaction with Miz-1.
Gfi-1 is a nuclear zinc finger (ZF) transcriptional repressor that plays an important role in hematopoiesis and inner ear development, and has been implicated in lymphomagenesis. Gfi-1 represses transcription by directly binding to the consensus DNA sequence in the promoters of its target genes. We report here an alternative mechanism by which Gfi-1 represses CDKN2B encoding p15(INK4B). Gfi-1 does not directly bind to CDKN2B, but interacts with Miz-1 and, via Miz-1, is recruited to the core promoter of CDKN2B. Miz-1 is a POZ-ZF transcription factor that has been shown to mediate transcriptional repression by c-Myc. Like c-Myc, upon recruitment to the CDKN2B promoter, Gfi-1 represses transcriptional activation of CDKN2B by Miz-1 and in response to TGFbeta. Consistent with its role in repressing CDKN2B transcription, knockdown of Gfi-1 in human leukemic cells or deficiency of Gfi-1 in mouse bone marrow cells results in augmented expression of p15(INK4B). Notably, Gfi-1 and c-Myc are both recruited to the CDKN2B core promoter and act in collaboration to repress CDKN2B. Our data reveal a mechanism of transcriptional repression by Gfi-1 and may have important implications for understanding the roles of Gfi-1 in normal development and tumorigenesis.
Basu
Suchitra
S
Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA.
Liu
Qingquan
Q
Qiu
Yaling
Y
Dong
Fan
F
D049109:Cell Proliferation; D002470:Cell Survival; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics* / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; C107961:ZBTB17 protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27