A recent report identified a patient presenting with clinical features of growth hormone insensitivity, who harbored a homozygous mis-sense mutation in the Stat5b gene that resulted in an alanine to proline substitution at amino acid 630, adjacent to the SH2 domain. The precise molecular defect caused by the mutant Stat5b protein has not been elucidated. Preliminary experiments have demonstrated that the mutant Stat5b protein is detected upon transient transfection in cultured mammalian cells, however at consistently <50% the level of wild-type Stat5b protein. In reconstitution experiments, mutant Stat5b failed to enhance reporter gene activity upon growth hormone stimulation. This research proposal attempts to identify the specific molecular defect of the mutant Stat5b in its inactivation cycle, highlighting two hypothesized areas of dysfunction. The first specific aim addresses protein stability and subcellular location of mutant Stat5b. The second specific aim focuses on whether the function of the nearby SH2 domain is disrupted, such that the mutant Stat5b can not interact with the activated growth hormone receptor/Jak2 complex or with other Stat5b molecules in the dimerization process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DK070447-01
Application #
6885085
Study Section
Special Emphasis Panel (ZRG1-F06 (20))
Program Officer
Hyde, James F
Project Start
2005-02-25
Project End
2007-02-24
Budget Start
2005-02-25
Budget End
2006-02-24
Support Year
1
Fiscal Year
2005
Total Cost
$55,352
Indirect Cost
Name
Oregon Health and Science University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Vidal, Oscar M; Merino, Roxana; Rico-Bautista, Elizabeth et al. (2007) In vivo transcript profiling and phylogenetic analysis identifies suppressor of cytokine signaling 2 as a direct signal transducer and activator of transcription 5b target in liver. Mol Endocrinol 21:293-311
Chia, Dennis J; Ono, Mitsuru; Woelfle, Joachim et al. (2006) Characterization of distinct Stat5b binding sites that mediate growth hormone-stimulated IGF-I gene transcription. J Biol Chem 281:3190-7
Chia, Dennis J; Subbian, Ezhilkani; Buck, Teresa M et al. (2006) Aberrant folding of a mutant Stat5b causes growth hormone insensitivity and proteasomal dysfunction. J Biol Chem 281:6552-8