Growth factor independence-1 (Gfi-1): Evaluating the role of Gfi-1 interaction with Miz-1 in the repression of p15INK4B and its involvement in BCR/ABL-mediated transformation. Suchitra Basu

ISBN: 9781109037357

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90 pages


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Growth factor independence-1 (Gfi-1): Evaluating the role of Gfi-1 interaction with Miz-1 in the repression of p15INK4B and its involvement in BCR/ABL-mediated transformation.  by  Suchitra Basu

Growth factor independence-1 (Gfi-1): Evaluating the role of Gfi-1 interaction with Miz-1 in the repression of p15INK4B and its involvement in BCR/ABL-mediated transformation. by Suchitra Basu
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Growth Factor Independence-1 (Gfi-1) is a nuclear transcriptional repressor that plays an important role in hematopoiesis, inner ear development and has been implicated in lymphomagenesis. Gfi-1 is critical for the development of T cells, B cells andMoreGrowth Factor Independence-1 (Gfi-1) is a nuclear transcriptional repressor that plays an important role in hematopoiesis, inner ear development and has been implicated in lymphomagenesis. Gfi-1 is critical for the development of T cells, B cells and neutrophils.

Gfi-1 deficient mice show defective T and B cell development and lack mature neutrophils. Interestingly, Gfi-1 promotes proliferation and has been shown to be overexpressed in bone marrow (BM) cells of Chronic Myeloid Leukemia (CML) patients. Our present study is aimed at addressing the mechanism of transcriptional repression by Gfi-1 and investigates the role of Gfi-1 in BCR/ABL mediated transformation.-Gfi-1 represses transcription by directly binding to the consensus DNA sequence in the promoters of its target genes.

Here, we report an alternative mechanism by which Gfi-1 represses the cyclin-dependent kinase inhibitor gene CDKN2B (p15INK4B) encoding pl5INK4B. Gfi-1 does not directly bind to p15INK4B, but interacts with Miz-1 and, via Miz-1, is recruited to the core promoter of p15INK4B. Miz-1 is a POZ-ZF transcription factor with strong anti-growth function and has been shown to mediate transcriptional repression by c-Myc.

Like c-Myc, upon recruitment to the p15INK4B promoter, Gfi-1 represses transcriptional activation of p15INK4B by Miz-1. Consistent with its role in repressing p15INK4B transcription, knockdown of Gfi-1 in human leukemic cells or deficiency of Gfi-1 in mouse bone marrow cells results in augmented expression of p15INK4B.

Notably, Gfi-1 and c-Myc are both recruited to the p15INK4B core promoter and act in collaboration to repress p15INK4B. Our data reveals a novel mechanism of transcriptional repression by Gfi-1 and may have important implications for understanding the roles of Gfi-1 in normal development and tumorigenesis.-The role of Gfi-1 in BCR/ABL mediated transformation was investigated initially by examining the effect of overexpression of the dominant negative mutant of Gfi-1, N382S, on BCR/ABL mediated transformation in myeloid 32D cells.

Our results show that expression of N382S in BCR/ABL expressing 32D cells inhibited cell growth and caused rapid apoptosis, which was associated with altered expression of Bcl-2 family members Bad and Mcl-1. The expression of N382S also dramatically increased the sensitivity of 32DBCR/ABL cells to imatinib, a c-ABL kinase inhibitor.

Silencing of Gfi-1 inhibited BCR/ABL-dependent proliferation and survival in both 32D and Mole cells. Taken together, these data indicate that Gfi-1 may play an important role in BCR/ABL mediated transformation and identifies Gfi-1 as a potential therapeutic target in the treatment of CML.



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