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Professor of Cell and Developmental Biology*
*And Faculty Scientist, Lawrence Berkeley National Laboratory, Division of Life Sciences
We are interested in the signal transduction pathways downstream of the transforming growth factor β (TGFβ) receptors and the role these pathways play in regulation of mammalian epithelial cell growth, differentiation, apoptosis and carcinogenesis. We wish to understand how TGFβ induces a wide range of biological activities and identify components of the TGFβ receptor signaling pathways.
The TGFβ family of cytokines, including TGFβs, Nodal, activins and BMPs, plays important roles in tumor suppression, cell differentiation and tissue morphogenesis, and extracellular matrix production. They exert diverse effects through the cell surface types I and II receptors, which possess serine/threonine kinase activities, and downstream Smad proteins. The Smad proteins are transcription factors that upon phosphorylation by the type I receptor kinases, accumulate in the nucleus and regulate the expression of target genes. The activity of the Smad proteins are subjected to regulation by various cellular co-factors. SnoN and the related Ski proteins are critical negative modulators of the Smads by binding to and repressing their transcription activities.
SnoN and Ski play important and complex roles in human cancer and embryonic development. In many types of human cancer including breast cancer, lung cancer, esophageal, lymphoma, colon cancer and melanoma, their expression was deregulated. We have shown recently that these proteins possess both oncogenic and tumor suppressor activities by regulating the proliferation, survival and senescence of cells. We found that in addition to modulating TGFβ signaling, SnoN can also activate the p53 pathway, through which it may regulate tumor progression, regeneration and ageing.
We are interested in understanding the functions of TGFβ signaling and in particular, SnoN and Ski, in tumorigenesis, development and ageing using both tissue culture cell lines and mouse models, with an emphasis on mammary gland development and breast cancer. Our current research focused on the following areas:
Understanding the role of TGFβ signaling/SnoN in mammary epithelial cell differentiation and breast cancer We are employing three model systems for this study: 1) normal and cancerous mammary epithelial cells lines, allowing us to perform biochemical characterizations; 2) a three-dimensional matrigel culture (3D) model, allowing us to examine the regulation of cell proliferation, polarity, apoptosis and differentiation in an integrated system and offering a highly sensitive assay for breast cancer transformation; 3) transgenic and knockout/knockin mouse models, providing insights on the in vivo biological functions of these molecules.
Understanding the signaling mechanisms SnoN/Ski and its implication in physiological functions In addition to antagonizing the Smad proteins, we have recently uncovered a novel pathway by which SnoN activates p53 in a PML-dependent manner to regulate cell senescence. It is possible that SnoN and Ski may modulate other important cellular pathways and mediate crosstalk between TGFβ signaling and other pathways. Its own activity, expression and localization may also be regulated by additional pathways. Using biochemical approaches, we are trying to uncover these pathways and regulatory mechanisms that govern SnoN/Ski function and expression.
Understanding the functions SnoN/Ski in embryonic development We have generated knockout and knockin mice of the snoN and ski genes. Some of the mice showed partial embryonic lethality due to defects in angiogenesis and/or early patterning. Analysis of the phenotypes of these mice uncovers previously unidentified functions of SnoN and Ski.Understanding the functions of SnoN/Ski in regeneration and ageing We are investigating the functions of SnoN and Ski in muscle stem cell regeneration and organism ageing using the knockin and knockout mice.
SnoN functions as a tumor suppressor by inducing premature senescence. [D. Pan, Q. Zhu, and K. Luo (2009) EMBO J. In press.]
TGF-β suppresses the ability of Ski to inhibit tumor metastasis by inducing its degradation. [E. Le Scolan, Q. Zhu, L. Wang, A. Bandyopadhyay, D. Javelaud, A. Mauviel, L. Sun, and K. Luo (2008) Cancer Res. 68: 3277-3285.]
Dual Role of SnoN in mammalian tumorigenesis. [Q. Zhu, A.R. Krakowski, E.E. Dunham, L.L. Wang, A. Bandyopadhyay, R. Berdeaux, G.S. Martin, L. Sun, and K. Luo (2007) Mol. Cell. Biol. 27: 324-39.]
SnoN mediates TGFβ-induced oncogenic transformation of fibroblast cells. [Q. Zhu, S. Pearson-White, and K. Luo (2005) Mol. Cell. Biol. 25: 10731-44.]Cytoplasmic SnoN in normal cells and non-malignant tissues antagonizes TGFβ signaling through sequestration of the Smad proteins. [A.R. Krakowski, J. Laboureau, A. Mauviel,M.J. Bissell, and K. Luo (2005) Proc. Natl. Acad. Sci. 102: 12437-12442.]
Ski and SnoN: negative regulators of TGFβ signaling. [K. Luo (2004) Curr. Op. Gen. Dev. 14, 65-70.]Akt interacts directly with Smad3 to regulate the sensitivity to TGFβ-induced apoptosis. [A. Conery, Y. Cao, E.A. Thompson, C.M. Townsend Jr, T.C. Ko, and K. Luo (2004) Nature Cell Biology 6, 366-72.]
Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: Insights on Ski-mediated repression of TGF-β signaling. [J.-W. Wu, A. R. Krawitz, J. Chai, W. Li, F. Zhang, K. Luo and Y. Shi (2002) Cell 110, 357-367.]Smad3 recruits the anaphase promoting complex for ubiquitination and degradation of SnoN [S. L. Stroschein, S. Bonni, J. L. Wrana and K. Luo (2001) Genes & Development 15, 2822-2836]
TGFβ induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. [S. Bonni, H.-R. Wang, C. G. Causing, P. Kavsak, S. L. Stroschein, K. Luo and J. L. Wrana (2001) Nature Cell Biology 3, 587-595]Ski represses BMP signaling to induce neural cell fate. [W. Wang, F. V. Mariani, R. M. Harland and K. Luo (2000) Proc. Natl. Acad. Sci. 97, 14394-14399]
Negative feedback regulation of TGFβ signaling by the SnoN oncoprotein. [S. L. Stroschein, W. Wang, S. Zhou, Q. Zhou, and K. Luo (1999) Science 286, 771-774]Last Updated 2009-08-03