Michael B. Datto, MD, PhD

Department / Division:
Pathology / Pathology

Address:
DUMC 3712
Durham, NC 27710

Office Telephone:
(919) 684-6965

Fax Telephone:
(919) 684-6962

• M.D., Duke University Medical Center, North Carolina, 1999

• Pathology, Duke University Medical Center, North Carolina, 2004

• Ph.D., Molecular Cancer Biology, Duke University Medical Center, North Carolina, 1999

Clinical Interests:
Molecular diagnostic testing

Research Interests:
Transforming growth factor beta (TGF-β) is a multifunctional protein hormone that signals through a complex system of receptors, Smads and a constantly growing array of Smad and receptor interacting proteins. The need for this complexity becomes clear in light of the diverse roles of TGF-β and the TGF-β superfamily in nearly all aspects of biology in all stages of life. Throughout life, TGF-β family members control a variety of physiological processes including immune responses, bone formation, and wound healing to name a few. In additoin, TGF-β and proteins involved in TGF-β signaling are tumor suppressor genes that are lost or inactivated in a variety of epithelial and lymphoid neoplasms. Our laboratory takes a combined genomic, proteomic and mouse models approach to understanding the complexity that underlies the cell type specific and context specific nature of TGF-β signaling. Specifically, using mice that harbor a targeted disruption of the Smad3 gene, we have identified a number of biological and cellular responses to TGF-β that are independent of Smad3 function, and that occur in a cell type specific or context dependent fashion. Using mRNA expression profiling in these systems, we are identifying genes that are transcriptionally regulated independent of Smad signaling. Coupled with these genomic approaches, we are also employing state of the art phosphoproteome profiling and expression proteome profiling techniques to identify novel substrates of the TGF-β receptor kinases.

In addition to using these proteome profiling techniques to answer basic science questions of signal transduction, we are also applying these approaches to a second clinically focused project, namely the identification of disease markers using state of the art mass spectrometry based proteome profiling for diagnosis or prognosis in a variety of disease states. This is a new project in the laboratory which is greatly facilitated by our close ties to the DUMC Clinical Molecular Diagnostics Laboratory.

Representative Publications:
Datto MB, Yu Y, Wang XF. Functional analysis of the transforming growth factor beta responsive elements in the WAF1/Cip1/p21 promoter. J Biol Chem. 1995 Dec 1;270(48):28623-8. (1995) Abstract

Liberati NT, Datto MB, Frederick JP, Shen X, Wong C, Rougier-Chapman EM, Wang XF. Smads bind directly to the Jun family of AP-1 transcription factors. Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4844-9. (1999) Abstract

Borton AJ, Frederick JP, Datto MB, Wang XF, Weinstein RS. The loss of Smad3 results in a lower rate of bone formation and osteopenia through dysregulation of osteoblast differentiation and apoptosis. J Bone Miner Res. 2001 Oct;16(10):1754-64. (2001) Abstract

Li JM, Datto MB, Shen X, Hu PP, Yu Y, Wang XF. Sp1, but not Sp3, functions to mediate promoter activation by TGF-beta through canonical Sp1 binding sites. Nucleic Acids Res. 1998 May 15;26(10):2449-56. (1998) Abstract

Datto MB, Hu PP, Kowalik TF, Yingling J, Wang XF. The viral oncoprotein E1A blocks transforming growth factor beta-mediated induction of p21/WAF1/Cip1 and p15/INK4B. Mol Cell Biol. 1997 Apr;17(4):2030-7. (1997) Abstract

Yingling JM, Datto MB, Wong C, Frederick JP, Liberati NT, Wang XF. Tumor suppressor Smad4 is a transforming growth factor beta-inducible DNA binding protein. Mol Cell Biol. 1997 Dec;17(12):7019-28. (1997) Abstract

Schwarz JK, Bassing CH, Kovesdi I, Datto MB, Blazing M, George S, Wang XF, Nevins JR. Expression of the E2F1 transcription factor overcomes type beta transforming growth factor-mediated growth suppression. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):483-7. (1995) Abstract

Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF. Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J Biol Chem. 1999 Dec 3;274(49):35053-8. (1999) Abstract

Shen X, Hu PP, Liberati NT, Datto MB, Frederick JP, Wang XF. TGF-beta-induced phosphorylation of Smad3 regulates its interaction with coactivator p300/CREB-binding protein. Mol Biol Cell. 1998 Dec;9(12):3309-19. (1998) Abstract

Decesse JT, Medjkane S, Datto MB, Crémisi CE. RB regulates transcription of the p21/WAF1/CIP1 gene. Oncogene. 2001 Feb 22;20(8):962-71. (2001) Abstract

Wong C, Rougier-Chapman EM, Frederick JP, Datto MB, Liberati NT, Li JM, Wang XF. Smad3-Smad4 and AP-1 complexes synergize in transcriptional activation of the c-Jun promoter by transforming growth factor beta. Mol Cell Biol. 1999 Mar;19(3):1821-30. (1999) Abstract

Datto M, Wang XF. The Smads: transcriptional regulation and mouse models. Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):37-48. (2000) Abstract

Datto MB, Frederick JP, Pan L, Borton AJ, Zhuang Y, Wang XF. Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. Mol Cell Biol. 1999 Apr;19(4):2495-504. (1999) Abstract

Kivinen L, Tsubari M, Haapajärvi T, Datto MB, Wang XF, Laiho M. Ras induces p21Cip1/Waf1 cyclin kinase inhibitor transcriptionally through Sp1-binding sites. Oncogene. 1999 Nov 4;18(46):6252-61. (1999) Abstract

Datto M, Wang XF. Ubiquitin-mediated degradation a mechanism for fine-tuning TGF-beta signaling. Cell. 2005 Apr 8;121(1):2-4. (2005) Abstract

Haapajärvi T, Kivinen L, Heiskanen A, des Bordes C, Datto MB, Wang XF, Laiho M. UV radiation is a transcriptional inducer of p21(Cip1/Waf1) cyclin-kinase inhibitor in a p53-independent manner. Exp Cell Res. 1999 Apr 10;248(1):272-9. (1999) Abstract

Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5545-9. (1995) Abstract

Hu PP, Datto MB, Wang XF. Molecular mechanisms of transforming growth factor-beta signaling. Endocr Rev. 1998 Jun;19(3):349-63. (1998) Abstract

Billon N, Carlisi D, Datto MB, van Grunsven LA, Watt A, Wang XF, Rudkin BB. Cooperation of Sp1 and p300 in the induction of the CDK inhibitor p21WAF1/CIP1 during NGF-mediated neuronal differentiation. Oncogene. 1999 May 6;18(18):2872-82. (1999) Abstract

Zhao J, Shi W, Wang YL, Chen H, Bringas P Jr, Datto MB, Frederick JP, Wang XF, Warburton D. Smad3 deficiency attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Physiol Lung Cell Mol Physiol. 2002 Mar;282(3):L585-93. (2002) Abstract