Many studies have indicated that aberrant recruitment of histone deacetylases (HDACs) may lead to cancer. HDACs are thought to function, in part, by regulating transcriptional activity of DNA-binding transcription factors thereby modulating the expression of a network of genes. Thus, understanding how HDACs regulate transcription and how cellular signaling controls HDAC activity will help to understand deregulated cell growth in cancer and may have therapeutic implications for cancer treatment. HDAC7 (Histone deacetylase 7) belongs to the class II HDACs that includes HDAC4, -5, -6, -9, and -10. Members of the class II HDACs distinguish themselves from class I HDACs by their restricted tissue distribution profiles and notably, their ability to shuttle between the nucleus and the cytoplasm. We hypothesize that the subcellular distribution of HDAC7 is determined by the interplay between its interacting partners.
Aim I will elucidate the mechanism of nucleocytoplasmic shuttling of HDAC7.
Aim II will characterize the proteolytic pathway regulating HDAC7 degradation. We also discovered that 14-3-3 proteins stabilize HDAC7.
Aim III will dissect the mechanism of 14-3-3-dependent stabilization of HDAC7. A combination of fluorescence microscopy, inhibitor, and biochemical approaches will be taken to accomplish these objectives. The results from this study will determine the mechanism by which HDAC7 activity is regulated at the molecular and cellular level. Understanding how cellular signaling controls HDAC activities will help to understand deregulated cell growth in cancer and may have therapeutic implications for cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK062985-01A1
Application #
6684616
Study Section
Biochemistry Study Section (BIO)
Program Officer
Margolis, Ronald N
Project Start
2003-08-01
Project End
2007-05-31
Budget Start
2003-08-01
Budget End
2004-05-31
Support Year
1
Fiscal Year
2003
Total Cost
$263,543
Indirect Cost
Name
Case Western Reserve University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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