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 TGF. 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.cyclin-dependent kinase inhibitor ͉ proliferation ͉ transcriptional repressor ͉ tumorigenesis
Zinc-finger (ZF) transcriptional repressor Gfi-1 plays 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 p21Cip1 has been identified as a Gfi-1 target gene and 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 via Miz-1 binds to CDKN1A core promoter. Interestingly, Gfi-1 and c-Myc, through Miz-1, form a ternary complex on the CDKN1A promoter, and act in collaboration to repress CDKN1A. Gfi-1 knockdown results in enhanced levels of p21Cip1 and attenuated cell proliferation. Notably, similar to c-Myc, the expression of Gfi-1 is downregulated by TGFβ and the level of Gfi-1 influences the response of cell to the cytostatic effect of TGFβ. 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.
The Aluminum (Al) and proton (H ) ions are major acid soil stress factors deleteriously affecting plant root growth and crop yield. In our preliminary studies, cotton seedlings (Gossypium hirsutum L.) displayed very sensitive phenotypes to Al and H rhizotoxicities. Based on previous Arabidopsis results, we aimed to characterize the Al stress responsive Sensitive to Proton rhizotoxicity 1 (GhSTOP1) transcription system in cotton by RNAi mediated down-regulation. With the help of seed embryo apex explants, we developed transgenic cotton plants overexpressing a GhSTOP1-RNAi cassette with NPTII selection. Kanamycin tolerant T1 seedlings were further considered for Al and H stress tolerance studies. Down-regulation of the GhSTOP1 displayed increased sensitivity to Al and proton rhizotoxicities and the root growth was significantly reduced in RNAi-lines. The expression profile of GhALMT1 (Aluminum-activated Malate Transporter 1), GhMATE (Multidrug and Toxic Compound Extrusion), GhALS3 (Aluminum Sensitive 3) and the key genes involved in the GABA shunt were downregulated in the transgenic RNAi lines. Additionally, the lateral root initiation process was delayed and the expression of GhNAC1 which is involved in lateral root initiation was also suppressed in transgenic lines. Besides, overexpression of GhSTOP1 in Arabidopsis accelerated root growth and AtMATE and AtALMT1 expression under Al stress conditions. These analyses indicate that the GhSTOP1 is necessary for the expression of several genes which are necessary for acid soil tolerance mechanisms and lateral root initiation. This article is protected by copyright. All rights reserved.
Zinc finger (ZF) transcriptional repressor Gfi-1 plays 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 the consensus DNA sequence in the promoters of its target genes. We report here an alternative mechanism by which Gfi-1 represses CDKN2B encoding the cyclin-dependent kinase inhibitor p15INK4B. Gfi-1 did not directly bind to CDKN2B, but interacted with Miz-1 and, via Miz-1, was recruited to the core promoter of CDKN2B. The C-terminal zinc finger domains of Gfi-1 and Miz-1 are involved in the interaction. 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 repressed transcriptional activation of CDKN2B by Miz-1 and in response to TGFb. Notably, Gfi-1 and c-Myc formed a ternary complex with Miz-1 and were both recruited to the CDKN2B core promoter via Miz-1, and acted in collaboration to repress CDKN2B. Consistent with its role in repressing CDKN2B transcription, knockdown of Gfi-1 in human leukemic cells resulted in augmented levels of p15INK4B, which was associated with attenuated cell proliferation. The expression of p15INK4B was also significantly higher in Gfi-1−/− mouse bone marrow (BM) cells than in Gfi-1+/+ BM cells. Our data reveal a novel mechanism of transcriptional repression by Gfi-1 and also identify CDKN2B as a new Gfi-1 target gene. The findings may have important implications for understanding the role of Gfi-1 in normal development and the cooperation between Gfi-1 and c-Myc in lymphomagenesis.
Chronic myelogenous leukemia (CML) is a clonal hematopoietic disorder caused by the BCR/ABL fusion oncogene. CML typically evolves in three distinct clinical stages: chronic and accelerated stages and blast crisis. The progression of CML from chronic phase (CP) to blast crisis (BC) is characterized by the increasing failure of myeloid precursors to differentiate into mature granulocytes and aggressive proliferation of immature myeloid cells. It has been shown that CML progression from CP to BC is associated with downregulation of C/EBPs including C/EBPa and C/EBPe, critical regulators of myeloid development. Forced expression of C/EBPs suppresses transformation and restores granulocytic differentiation of BCR/ABL-expressing myeloid cells, suggesting that downregulation of C/EBPs may be involved in CML transition from CP to BC. The proto-oncogene Gfi-1 encodes a nuclear zinc-finger transcriptional repressor that is required for the survival and proliferation of myeloid cells. We recently showed that expression of a dominant negative Gfi-1 mutant, N382S, led to markedly increased expression of C/EBPe in myeloid cells, suggesting that Cebpe encoding C/EBPe is a Gfi-1 target. We investigated the possibility that inhibition of Gfi-1 function in BCR/ABL-expressing cells may increase C/EBPe expression, thereby exerting a negative effect on BCR/ABL-mediated transformation. Myeloid 32D cells transfected with BCR/ABL (32D/BCR/ABL) are independent of IL-3 for proliferation and survival. Expression of the N382S mutant in 32D/BCR/ABL cells (32D/N382S) had a significant inhibitory effect on proliferation and survival in the absence of IL-3, but only a weak effect in the presence of IL-3, suggesting that the N382S mutant specifically inhibited BCR/ABL-mediated proliferation and survival. The level of C/EBPe protein was markedly augmented in 32D/N382S cells. Interestingly, when cultured in medium containing no growth factors, 32D/N382S cells exhibited certain features of macrophage differentiation including increased cell size, adherence to the surface of culture flasks, spreading and increased surface expression of macrophage differentiation marker F4/80. 32D/N382S cells also became more sensitive to c-ABL kinase inhibitor imatinib. These data indicate that Gfi-1 may play an important role in BCR/ABL-mediated transformation and thus represent a potential therapeutic target in the treatment of CML.
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