(revised by applicant): In the prostate, transforming growth factor-beta (TGFb) promotes growth arrest and apoptosis of epithelial cells and can either suppress or promotes tumor growth. The mechanisms by which TGFb mediates these processes are under intense investigation. TGFbl signals through promoting the binding and activation of the TGFb type I receptor (TbRI) by TbRII. Activated TbRI phosphorylates Smads 2 and 3, which promotes both their and Smad4's entry in the nucleus, where they directly or indirectly regulate transcription. A current dogma in this field is that TbRII signals only through activation of TbRI. Another dogma is that Smads are the critical trigger of virtually all TGF-b responses including growth arrest and apoptosis. However, accumulating evidence is strengthening the notion that TGFb activates a number of other kinases (i.e., MAPKs) independent of Smads. Despite these advances, nothing is known about how TbRI and TbRII activate such Smad-independent signal. We propose to test the following hypothesis: TbRII is critical to TGFb signal transduction not only through activating TbRI, that activates receptor Smads, but also by mediation of Smad-independent TGFb signals. We will test this hypothesis in prostatic epithelial cell lines by studying: i) the role of EGF in regulating TGFb responses, ii) the structural/functional basis of TbRI and TbRII and the role of Smads and MAPKs in the activation of AP-1, and iii) regulation of growth inhibition by constitutively activated Smads.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092102-04
Application #
7048628
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Jhappan, Chamelli
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$245,138
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Shankar, Eswar; Song, Kyung; Corum, Sarah L et al. (2016) A Signaling Network Controlling Androgenic Repression of c-Fos Protein in Prostate Adenocarcinoma Cells. J Biol Chem 291:5512-26
Wahdan-Alaswad, Reema S; Song, Kyung; Krebs, Tracy L et al. (2010) Insulin-like growth factor I suppresses bone morphogenetic protein signaling in prostate cancer cells by activating mTOR signaling. Cancer Res 70:9106-17
Song, Kyung; Wang, Hui; Krebs, Tracy L et al. (2010) DHT selectively reverses Smad3-mediated/TGF-beta-induced responses through transcriptional down-regulation of Smad3 in prostate epithelial cells. Mol Endocrinol 24:2019-29
Yang, Jiayi; Wahdan-Alaswad, Reema; Danielpour, David (2009) Critical role of Smad2 in tumor suppression and transforming growth factor-beta-induced apoptosis of prostate epithelial cells. Cancer Res 69:2185-90
Song, Kyung; Wang, Hui; Krebs, Tracy L et al. (2008) Androgenic control of transforming growth factor-beta signaling in prostate epithelial cells through transcriptional suppression of transforming growth factor-beta receptor II. Cancer Res 68:8173-82
Wang, H; Song, K; Krebs, T L et al. (2008) Smad7 is inactivated through a direct physical interaction with the LIM protein Hic-5/ARA55. Oncogene 27:6791-805
Garcia, Jorge A; Danielpour, David (2008) Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies. Mol Cancer Ther 7:1347-54
Yang, J; Song, K; Krebs, T L et al. (2008) Rb/E2F4 and Smad2/3 link survivin to TGF-beta-induced apoptosis and tumor progression. Oncogene 27:5326-38
Song, Kyung; Wang, Hui; Krebs, Tracy L et al. (2006) Novel roles of Akt and mTOR in suppressing TGF-beta/ALK5-mediated Smad3 activation. EMBO J 25:58-69
Song, Kyung; Krebs, Tracy L; Danielpour, David (2006) Novel permissive role of epidermal growth factor in transforming growth factor beta (TGF-beta) signaling and growth suppression. Mediation by stabilization of TGF-beta receptor type II. J Biol Chem 281:7765-74

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