): Transforming growth factor-beta1 (TGF-beta) is a growth factor with a variety of biological activities governing cell growth, production of extracellular matrix, development, and differentiation. Defects in TGF-beta signal transduction are implicated in a variety of diseases such as cancer and diabetic glomerulosclerosis. A fundamental effect of TGF-beta on cells is to regulate transcription of a broad range of genes. However, currently little is known about how TGF-beta regulates expression of a diverse range of genes and how it induces inhibition of cell growth. The applicant seeks to identify novel molecules in TGF-beta signaling pathway which activate the TGF-beta-induced gene transcription. This is made possible by taking advantage of an engineered TGF-beta responsive cell line and high-titer retroviral cDNA libraries. Novel molecules that inhibit TGF-beta signaling will also be identified using this system. The applicant will investigate how the uncovered novel molecules participate in TGF-beta signaling. Furthermore, to investigate the physiological role of a TGF-beta activated transcription factor, TFE3, this transcription factor will be knocked out in mice by homologous gene-targeting. Alternatively, transgenic mice expressing an inducible dominant negative TFE3 will be generated. Finally, an antisense RNA approach in concert with a specially designed retroviral cDNA library will be employed to isolate cDNAs encoding proteins that are essential for TGF-beta-induced growth inhibition. The novel cDNAs isolated by the antisense approach will be tested for its potential role as tumor suppressor genes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA078592-03
Application #
6174387
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
1998-07-01
Project End
2000-08-31
Budget Start
2000-07-01
Budget End
2000-08-31
Support Year
3
Fiscal Year
2000
Total Cost
$26,027
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
076580745
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Schnepp, Robert W; Hou, Zhaoyuan; Wang, Haoren et al. (2004) Functional interaction between tumor suppressor menin and activator of S-phase kinase. Cancer Res 64:6791-6
La, Ping; Schnepp, Robert W; D Petersen, Clark et al. (2004) Tumor suppressor menin regulates expression of insulin-like growth factor binding protein 2. Endocrinology 145:3443-50
Schnepp, Robert W; Mao, Hua; Sykes, Stephen M et al. (2004) Menin induces apoptosis in murine embryonic fibroblasts. J Biol Chem 279:10685-91
La, Ping; Morgan, Trish A; Sykes, Stephen M et al. (2003) Fusion proteins of retinoid receptors antagonize TGF-beta-induced growth inhibition of lung epithelial cells. Oncogene 22:198-210
Jin, Shenghao; Mao, Hua; Schnepp, Robert W et al. (2003) Menin associates with FANCD2, a protein involved in repair of DNA damage. Cancer Res 63:4204-10
Hua, X; Miller, Z A; Benchabane, H et al. (2000) Synergism between transcription factors TFE3 and Smad3 in transforming growth factor-beta-induced transcription of the Smad7 gene. J Biol Chem 275:33205-8
Hua, X; Miller, Z A; Wu, G et al. (1999) Specificity in transforming growth factor beta-induced transcription of the plasminogen activator inhibitor-1 gene: interactions of promoter DNA, transcription factor muE3, and Smad proteins. Proc Natl Acad Sci U S A 96:13130-5