Pran K. Datta, Ph.D.
Vanderbilt University Medical Center
D-2300 Medical Center North
Nashville, TN 37232-2733
Role of TGF-ß/Smad7/STRAP signaling in tumor suppression and promotion.
Members of the TGF-ß family regulate a wide range of biological processes including cellular proliferation, cell migration, differentiation, apoptosis, and extracellular matrix deposition. The research in my laboratory focuses on the transforming growth factor-ß (TGF-ß) signal transduction pathways and the role of signaling molecules involved in these pathways in tumor suppression and promotion. Recently, we have cloned a novel WD-40 domain containing protein, called STRAP (Serine Threonine Kinase Receptor Associated Protein), that associates with both TGF-ß type I receptor (TßRI) and type II receptor (TßRII). STRAP is involved in the negative regulation of TGF-ß signaling. STRAP synergizes with Smad7, an inhibitory Smad, in the inhibition of TGF-ß-induced tumor suppressor functions. STRAP activates MAPK/ERK pathway, downregulats p21 Cip1, and C-terminus of STRAP is required for its phosphorylation and binding with two phospho-proteins. We have identified STRAP binding proteins by using Proteomics/Mass spectroscopy, and it will be interesting to determine the functional outcome of these interactions. Our long-term objective of this line of investigation is (1) to understand the role of STRAP in TGF-ß signaling, (2) to determine how this protein is involved in the crosstalk between TGF-ß and other signaling cascades and (3) to study the function of STRAP in vivo by Cre-lox targeted deletion of the STRAP gene .
We have observed that STRAP is upregulated in 45% of breast cancers, 70% of colorectal cancers and 75% of lung cancers. STRAP induces anchorage-independent growth and enhances tumorigenicity in nude mice. Overexpression of Smad7 in cell culture model blocks TGF-ß signaling and promotes cell proliferation. The expression of Smad7 is increased in human pancreatic cancer. The current studies address the following issues: (1) to determine the role of STRAP and Smad7 in cellular proliferation and tumorigenicity, (2) to study the contribution of functional synergy between STRAP and Smad7 in the progression of colorectal cancer and lung cancer, and (3) to study the effect of blocking TGF-ß signals in the intestine by conditionally knocking out TßRII. For this study we are using transgenic mice that carry a floxed TGF-ß RII gene.
Another focus of the lab is to understand the mechanism of downregulation of TßRII in human lung cancers that can be targeted by the inhibitors (that are in clinical trial) of epigenetic changes. We are also investigating in vivo the role of TGF-ß signaling in metastasis.
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- Samanta, D, Datta, PK Alterations in the Smad pathway in human cancers. Front Biosci, 171281-93, 2012.
- Samanta, D, Gonzalez, AL, Nagathihalli, N, Ye, F, Carbone, DP, Datta, PK Smoking Attenuates Transforming Growth Factor-Î²-Mediated Tumor Suppression Function through Downregulation of Smad3 in Lung Cancer. Cancer Prev Res (Phila), 2012.
- Halder, SK, Cho, YJ, Datta, A, Anumanthan, G, Ham, AJ, Carbone, DP, Datta, PK Elucidating the mechanism of regulation of transforming growth factor Î² Type II receptor expression in human lung cancer cell lines. Neoplasia, 13(10), 912-22, 2011.
- Kashikar, ND, Zhang, W, Massion, PP, Gonzalez, AL, Datta, PK Role of STRAP in regulating GSK3Î² function and Notch3 stabilization. Cell Cycle, 10(10), 1639-54, 2011.
- Reiner, J, Ye, F, Kashikar, ND, Datta, PK STRAP regulates c-Jun ubiquitin-mediated proteolysis and cellular proliferation. Biochem Biophys Res Commun, 407(2), 372-7, 2011.
- Reiner, JE, Datta, PK TGF-beta-dependent and -independent roles of STRAP in cancer. Front Biosci, 16105-15, 2011.
- Rachakonda, G, Sekhar KR, Jowhar D, Samson, PC, Wikswo, JP, Beauchamp, RD, Datta, PK, Freeman,ML. "Increased Cell Migration and Plasticity in Nrf2 Deficient Cancer Cell Lines.." Oncogene, 29(25), 3703-3714, 2010.
- Kashikar, ND, Reiner, J, Datta, A, Datta, PK Serine threonine receptor-associated protein (STRAP) plays a role in the maintenance of mesenchymal morphology. Cell Signal, 22(1), 138-49, 2010.
- Nagaraj, NS, Datta, PK Targeting the transforming growth factor-beta signaling pathway in human cancer. Expert Opin Investig Drugs, 19(1), 77-91, 2010.
- Zhang, B, Halder, SK, Kashikar, ND, Cho, YJ, Datta, A, Gorden, DL, Datta, PK Antimetastatic Role of Smad4 Signaling in Colorectal Cancer. Gastroenterology, 2009.
- Zhang, B, Halder, SK, Zhang, S, Datta, PK Targeting transforming growth factor-beta signaling in liver metastasis of colon cancer. Cancer Lett, 277(1), 114-20, 2009.
- Kashikar, ND and Datta, PK "STRAP: Serine-Threonine Kinase Receptor-Associated Protein." Encyclopedia of Cancer, Springer-Verlag, (Part 19), 2710-2713, 2008.
- Halder, SK, Rachakonda, G, Deane, NG, Datta, PK Smad7 induces hepatic metastasis in colorectal cancer. Br J Cancer, 99(6), 957-65, 2008.
- Datta, PK and Mann, JR "Transforming Growth Factor-beta Signaling Inhibitors in Cancer Therapy." TGF-beta in Cancer Therapy, The Humana Press Inc., Vol II573-587, 2008.
- Shiou, SR, Singh, AB, Moorthy, K, Datta, PK, Washington, MK, Beauchamp, RD, Dhawan, P Smad4 regulates claudin-1 expression in a transforming growth factor-beta-independent manner in colon cancer cells. Cancer Res, 67(4), 1571-9, 2007.
- Anumanthan, G, Halder SK, Friedman, DB, and Datta PK "Oncogenic STRAP Modulates the Function of Ewing Sarcoma Protein Through a Novel Mechanism." Cancer Research, 66(22), 2006.
- Halder, SK, Anumanthan, G, Maddula, R, Mann, J, Chytil, A, Gonzalez, AL, Washington, MK, Moses, HL, Beauchamp, RD, Datta, PK Oncogenic function of a novel WD-domain protein, STRAP, in human carcinogenesis. Cancer Res, 66(12), 6156-66, 2006.
- Anumanthan, G, Halder, SK, Friedman, DB, Datta, PK Oncogenic serine-threonine kinase receptor-associated protein modulates the function of Ewing sarcoma protein through a novel mechanism. Cancer Res, 66(22), 10824-32, 2006.
- Grau, AM, Datta, PK, Zi, J, Halder, SK, Beauchamp, RD Role of Smad proteins in the regulation of NF-kappaB by TGF-beta in colon cancer cells. Cell Signal, 18(7), 1041-50, 2006.
- Shiou, SR, Datta, PK, Dhawan, P, Law, BK, Yingling, JM, Dixon, DA, Beauchamp, RD Smad4-dependent Regulation of uPA Secretion and RNA Stability Associated with Invasiveness by Autocrine and Paracrine TGF-beta. J Biol Chem, 2006.
- Halder, SK, Beauchamp, RD, Datta, PK A specific inhibitor of TGF-beta receptor kinase, SB-431542, as a potent antitumor agent for human cancers. Neoplasia, 7(5), 509-21, 2005.
- Anumanthan, G, Halder, SK, Osada, H, Takahashi, T, Massion, PP, Carbone, DP, Datta, PK Restoration of TGF-beta signalling reduces tumorigenicity in human lung cancer cells. Br J Cancer, 93(10), 1157-67, 2005.
- Halder, SK, Beauchamp, RD, Datta, PK Smad7 induces tumorigenicity by blocking TGF-beta-induced growth inhibition and apoptosis. Exp Cell Res, 307(1), 231-46, 2005.
- Datta, P. K. and Moses, H. L "Purified and isolated serine-threonine kinase receptor associated protein and use of same in the modulation of the biological activity of TGF-ß." US Patent# 6770458, (), 2004.
- Mithani, Suhail K, Balch, Glen C, Shiou, Sheng-Ru, Whitehead, Robert H, Datta, Pran K, Beauchamp, R Daniel Smad3 has a critical role in TGF-beta-mediated growth inhibition and apoptosis in colonic epithelial cells. J Surg Res, 117(2), 296-305, 2004.
- Parker, M A, Deane, N G, Thompson, E A, Whitehead, R H, Mithani, S K, Washington, M K, Datta, P K, Dixon, D A, Beauchamp, R D Over-expression of cyclin D1 regulates Cdk4 protein synthesis. Cell Prolif, 36(6), 347-60, 2003.
- Yu, Bo, Datta, Pran K, Bagchi, Srilata Stability of the Sp3-DNA complex is promoter-specific: Sp3 efficiently competes with Sp1 for binding to promoters containing multiple Sp-sites. Nucleic Acids Res, 31(18), 5368-76, 2003.
- Saha, D, Sekhar, KR, Cao, C, Morrow, JD, Choy, H, Freeman, ML The antiangiogenic agent SU5416 down-regulates phorbol ester-mediated induction of cyclooxygenase 2 expression by inhibiting nicotinamide adenine dinucleotide phosphate oxidase activity. Cancer Res, 63(20), 6920-7, 2003.
- Saha, D, Datta, P K, Beauchamp, R D Oncogenic ras represses transforming growth factor-beta /Smad signaling by degrading tumor suppressor Smad4. J Biol Chem, 27629531-7, 2001.
- Datta, P K, Blake, M C, Moses, H L Regulation of plasminogen activator inhibitor-1 expression by transforming growth factor-beta -induced physical and functional interactions between smads and Sp1. J Biol Chem, 27540014-9, 2000.
- Datta, P K, Moses, H L STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling. Mol Cell Biol, 203157-67, 2000.
- Saha, D, Datta, P K, Sheng, H, Morrow, J D, Wada, M, Moses, H L, Beauchamp, R D Synergistic induction of cyclooxygenase-2 by transforming growth factor-beta1 and epidermal growth factor inhibits apoptosis in epithelial cells. Neoplasia, 1508-17, 1999.
- Datta, P. K. "Direct submission of the nucleic acid sequence and the amino acid sequence of a novel protein, STRAP in GenBank." Accession number AF096285, October 1, 1998.
- Datta, P K, Chytil, A, Gorska, A E, Moses, H L Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signaling. J Biol Chem, 27334671-4, 1998.
- Engel, M E, Datta, P K, Moses, H L RhoB is stabilized by transforming growth factor beta and antagonizes transcriptional activation. J Biol Chem, 2739921-6, 1998.
- Engel, M E, Datta, P K, Moses, H L Signal transduction by transforming growth factor-beta: a cooperative paradigm with extensive negative regulation. J Cell Biochem Suppl, 30-31111-22, 1998.
- Datta, P K, Raychaudhuri, P, Bagchi, S Association of p107 with Sp1: genetically separable regions of p107 are involved in regulation of E2F- and Sp1-dependent transcription. Mol Cell Biol, 155444-52, 1995.
- Datta, P K, Bagchi, S Repression of transforming growth factor beta 1 promoter by the adenovirus oncogene E1A. Identification of a unique GC-rich sequence as a target for E1A repression. J Biol Chem, 26925392-9, 1994.