Vitamin D3 inducible Genes Mediating Differentiation

Project: Research project

Project Details

Description

DESCRIPTION: (Scanned from the applicant's abstract) The goal of this competing
renewal is to further our elucidation of the molecular events leading to
myeloid leukemic cell differentiation in response to the hormone 1,25
dihydroxyvitamin D3 [1 ,25(OH)2D3}. We will focus on two vitamin D receptor
(VDR? target genes central to the induction of growth arrest and
differentiation in the myeloid cell system: p21waf1,cip, and HoxAlO. In
addition, myeloid differentiation will be used as cellular readout for the 1
,25(OH)2D3 response in the context of nuclear receptor coactivator function, as
well as when VDR function is attenuated by chromosomal translocations involving
the RARa gene. The specific aims during the proposed grant period are to: 1.
Characterize the complex regulation of the p21 promoter by VDR and HoxAlO, A
cluster of multiple VDr and HoxAlO binding sites in the p21 promoter
individually and collectively contribute to 1,25(OH)2D3 regulation of this
promoter. Nucleosomal structure and in viva occupancy of these regions will be
examined in response to 1,25(OH)2D3 and HoxAlO. 2.Define the role of HoxAlO in
growth arrest and cell differentiation. HoxAlO regulation of the p21 promoter,
and its possible role as a transcriptional modulator of other cell cycle
regulator genes, will be addressed. A screen for novel HoxAlO target genes
using array technology will also be generated. 3. Describe the molecular basis
for PLZF and PLZF-RARcx attenuation of 1,25 (OH)2D3-inducible myeloid
differentiation. The mechanisms by which 1 ,25(OH)2D3-dependent differentiation
is attenuated by PLZF and PLZFRARa will be characterized at the molecular
level. 4. Utilize cell differentiation as a biological read-out for coactivator
function. The functional requirement of the DRIP coactivator complex in
mediating VDR and RAR transactivation, in the context of nuclear
receptor-dependent myeloid differentiation, will be determined.
StatusFinished
Effective start/end date5/27/974/30/06

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $285,250.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $285,250.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $285,250.00

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