Activin is a member of the TGF-beta superfamily of cytokines and exhibits a large variety of biological activities. Studies on the regulation of activin function are not only important for understanding the physiological activities of activin, but also helpful for future research on potential clinical application when modification of activin function is beneficial to the patient. Our preliminary studies showed that Smad7 is a novel intracellular regulator of activin signaling. The objective of this proposal is to determine the molecular mechanisms underlying the regulation of activin activity by Smad7 and the regulation of Smad7 expression at the transcriptional level. We will pursue the following specific aims: (1) To characterize the molecular mechanism by which Smad7 regulates activin signaling. We will determine if the interaction of Smad7 with activin type I receptor ALK-4 is required for the inhibitory activity of Smad7. We will use a series of structural mutants of Smad7 and ALK-4 to determine the interaction domains of these two proteins. Furthermore, we will examine the regulation of Smad7/ALK-4 interaction by the phosphorylation of the activin type I receptor. (2) To determine the regulatory effect of Smad7 on activin-mediated anti-proliferative activity. We will use hepatocytes and prostate cancer cells as a model system to determine the regulatory effect of Smad7 on the growth-inhibitory activity of activin in these cells. We will determine the mechanism underlying the activin-mediated regulation of cell cycle control machinery. We will then determine if ectopic expression of Smad7 is able to modulate this regulatory role of activin on these cells. (3) To determine the regulation of Smad7 transcription by activin signaling. We will determine if Smad7 mRNA is upregulated by activin in these cells. If activin were able to regulate Smad7 expression at the transcriptional level, we will characterize the promoter of Smad7 and identify the DNA element within the promoter that mediates the activin response. In conclusion, these studies would provide valuable information on the regulatory effect Smad7 on activin function at both the cellular and molecular levels.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Sato, Sheryl M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
Zip Code
Liu, Xubao; Chen, Qian; Kuang, Chenzhong et al. (2007) A 4.3 kb Smad7 promoter is able to specify gene expression during mouse development. Biochim Biophys Acta 1769:149-52
Kuang, Chenzhong; Xiao, Yan; Liu, Xubao et al. (2006) In vivo disruption of TGF-beta signaling by Smad7 leads to premalignant ductal lesions in the pancreas. Proc Natl Acad Sci U S A 103:1858-63
Lin, Lin; Qian, Yong; Shi, Xianglin et al. (2005) Induction of a cell stress response gene RTP801 by DNA damaging agent methyl methanesulfonate through CCAAT/enhancer binding protein. Biochemistry 44:3909-14
Lin, Lin; Stringfield, Teresa M; Shi, Xianglin et al. (2005) Arsenite induces a cell stress-response gene, RTP801, through reactive oxygen species and transcription factors Elk-1 and CCAAT/enhancer-binding protein. Biochem J 392:93-102
Kuang, Chenzhong; Chen, Yan (2004) Tumor-derived C-terminal mutations of Smad4 with decreased DNA binding activity and enhanced intramolecular interaction. Oncogene 23:1021-9
Ogawa, Kenji; Chen, Feifei; Kuang, Chenzhong et al. (2004) Suppression of matrix metalloproteinase-9 transcription by transforming growth factor-beta is mediated by a nuclear factor-kappaB site. Biochem J 381:413-22
Ogawa, Kenji; Chen, Feifei; Kim, Young-June et al. (2003) Transcriptional regulation of tristetraprolin by transforming growth factor-beta in human T cells. J Biol Chem 278:30373-81
Chen, Feifei; Ogawa, Kenji; Nagarajan, Raman P et al. (2003) Regulation of TG-interacting factor by transforming growth factor-beta. Biochem J 371:257-63
Liu, Xubao; Nagarajan, Raman P; Vale, Wylie et al. (2002) Phosphorylation regulation of the interaction between Smad7 and activin type I receptor. FEBS Lett 519:93-8
Chen, Feifei; Ogawa, Kenji; Liu, Xubao et al. (2002) Repression of Smad2 and Smad3 transactivating activity by association with a novel splice variant of CCAAT-binding factor C subunit. Biochem J 364:571-7

Showing the most recent 10 out of 11 publications