The Gfi-1 proto-oncogene is activated by provirus integration in T cell lymphoma lines selected for IL-2 independence in culture and in primary retrovirus-induced thymomas and collaborates with c-myc and pim-1 in oncogenesis. Gfi-1 encodes a zinc finger protein with six C2H2 type, C-terminal zinc finger motifs. The investigator s recent studies have shown that Gfi-1 is a 55 kD nuclear protein that binds DNA in a sequence specific manner and functions as a position and orientation independent active transcriptional repressor. Repressor activity depends on a novel twenty amino acid N-terminal repressor domain, coincident with a nuclear localization motif. The sequence of the Gfi-1 repressor domain is related to the sequence of the repressor domain of Gfi-1B, a Gfi-1 related protein, and to sequences at the N-termini of the insulinoma-associated protein, IA-1, the homeobox protein Gsh-1 and the vertebrate members of the Snail-Slug protein family. Among the genes repressed by Gfi-1 are p21WAF1, encoding a cyclin dependent kinase inhibitor, and Bax, an inducer of apoptosis, both of which are upregulatd by the tumor suppressor gene p53. Gfi-1 mediated repression is associated with inhibition of cell death and abrogation of the G1 checkpoint induced by IL-2 withdrawal in T cells. Induction of Gfi-1 may therefore contribute to T-cell activation and tumor progression by promoting cell cycle progression and by increasing cell viability. The Gfi-1 related protein Gfi-1B is expressed transiently during primitive embryonic hematopoiesis. In adult animals it is expressed in the less differentiated B and myeloid cells. Gfi-1B also represses expression of p21 and inhibits myeloid cell differentiation. He now proposes to examine the role of Gfi-1 and Gfi-1B in cell cycle progression, apoptosis, hematopoietic cell differentiation and oncogenesis, and to characterize functionally the Snail-Gfi-1 (SNAG) repressor domain. The long term objective of this project is to use Gfi-1 and Gfi-1B as probes to explore the biology of the hematopoietic system and the pathobiology of neoplasia with emphasis on cell cycle progression differentiation and apoptosis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Pathology B Study Section (PTHB)
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Cole, John S
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Thomas Jefferson University
Schools of Medicine
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