Annual Report 2011 - Center for Advanced Biotechnology and ...

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Dr. Fang Liu CABM Resident Faculty Member Associate Professor Department of Chemical Biology Ernest Mario School of Pharmacy Susan Lehman Cullman Laboratory for Cancer Research Rutgers University Growth and Differentiation Control Laboratory Dr. Fang Liu obtained her B.S. in biochemistry from Beijing University and Ph.D. in biochemistry from Harvard University working with Dr. Michael R. Green. She conducted postdoctoral research with Dr. Joan Massagué at Memorial Sloan-Kettering Cancer Center and joined CABM in 1998. Dr. Liu has received awards from the American Association for Cancer Research-National Foundation for Cancer Research, the Pharmaceutical Research and Manufacturers of America Foundation, the Burroughs Wellcome Fund, and the Sidney Kimmel Foundation for Cancer Research. She also obtained fellowships from the K.C. Wong Education Foundation and the Jane Coffin Childs Memorial Fund for Medical Research. We study TGF-ß/Smad signal transduction, transcriptional regulation, cell cycle control and their roles in cancer. TGF-ß regulates a wide variety of biological activities. It induces potent growth inhibitory responses in normal cells, but promotes migration and invasion of cancer cells. Smads mediate the TGF-ß responses. TGF-ß binding to the cell surface receptors leads to the phosphorylation of Smad2/3 in their carboxyl-terminus as well as in the proline-rich linker region. The serine/threonine phosphorylation sites in the linker region are followed by the proline residue. Pin1, a peptidyl-prolyl cis/trans isomerase, recognizes phosphorylated serine/threonine-proline (pS/T-P) motifs. We show that Smad2/3 interacts with Pin1 in a TGF-ß-dependent manner. We further show that the phosphorylated threonine 179-proline motif in the Smad3 linker region is the major binding site for Pin1. Although EGF also induces phosphorylation of threonine 179 and other residues in the Smad3 linker region the same as TGF-ß, Pin1 is unable to bind to the EGF-stimulated Smad3. Further analysis suggests that phosphorylation of Smad3 in the carboxyl-terminus is necessary for the interaction with Pin1. Depletion of Pin1 by shRNA does not affect significantly TGF-ß-induced growth-inhibitory responses and a number of TGF-ß/Smad target genes analyzed. In contrast, knockdown of Pin1 in human PC3 prostate cancer cells strongly inhibited TGF-ß-mediated migration and invasion. Accordingly, TGF-ß induction of Ncadherin, which plays an important role in migration and invasion, is markedly reduced when Pin1 is depleted in PC3 cells. The catalytic activity of Pin1 is essential for TGF-ß-induced migration and invasion (see Figure). Since Pin1 is overexpressed in many cancers, our findings highlight the importance of Pin1 in TGF-ß-induced migration and invasion of cancer cells. 19
Smad3 plays an important role in inhibiting cell proliferation and promoting apoptosis. Human Smad3 is localized near a hot spot mutation area for breast cancer and for several other types of cancers. We have found that Smad3 levels are reduced in human primary breast cancer samples and in human breast cancer cell lines. Importantly, Smad3 expression is high in normal breast stem cells but low in breast cancer stem cells. In addition, our preliminary studies indicate that 7,12dimethylbenz-[a]-anthracene (DMBA), a chemical carcinogen, induces mammary tumor formation at a much higher frequency in Smad3 -/- or Smad3 +/- mice than in Smad3 +/+ mice. Thus, we hypothesize that Smad3 has important tumor suppressor function for breast cancer. Breast cancer stem cells are CD44 + CD24 -/low . Although CD44 lacks its own signaling domain, it associates with and co-stimulates signaling by a number of growth factor receptors, such as Her2 and EGF receptor 1. CD44 is overexpressed in the vast majority of breast cancers. CD44 is not just a marker for breast cancer stem cells. It is necessary for breast tumor initiation, tumor growth, and metastasis. Knockdown of CD44 greatly reduces tumor-initiating frequency, tumor weight, and colony formation in soft agar assay. Disruption of tumor cell surface CD44 function induces apoptosis in metastatic mammary carcinoma cells in vivo. A predominant function of CD44 is to promote growth and to inhibit apoptosis. The growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Our preliminary studies have discovered that Smad3 potently represses CD44 transcription in mammary epithelial cells. Thus, we further hypothesize that Smad3 repression of CD44 expression is essential for its tumor suppressor activity, and that Smad3 and p53 cooperate to inhibit breast tumorigenesis. Our research is directed towards testing these hypotheses. Our findings will be highly significant for preventing and treating breast cancer. 20
Page 1: CENTER FOR ADVANCED BIOTECHNOLOGY A
Page 4 and 5: Director’s Overview CABM—25 and
Page 6 and 7: of Health, National Science Foundat
Page 8 and 9: Cell & Developmental Biology Labora
Page 10 and 11: protein metabolism/activity, such t
Page 12 and 13: Dr. Céline Gélinas CABM Resident
Page 14 and 15: (CHINJ, CINJ and CABM) and Lauri Go
Page 16 and 17: Dr. Masayori Inouye CABM Resident F
Page 18 and 19: Xu, Z., Mirochnitchenko, O., Xu, C.
Page 22 and 23: Publications: Matsuura, I., Chiang,
Page 24 and 25: In the prior year, we have made con
Page 26 and 27: Dr. James Millonig CABM Resident Fa
Page 28 and 29: We have mapped 5 different vl modif
Page 30 and 31: Dr. Arnold Rabson Director Child He
Page 32 and 33: Publications: Zheng, X., Cui, X.X.,
Page 34 and 35: polymerase II, facilitating the sel
Page 36 and 37: Dr. Mengqing Xiang CABM Resident Fa
Page 38 and 39: neurons diminish while there is a s
Page 40 and 41: Laboratory Faculty Director Structu
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Page 44 and 45: atomic detail and have yielded nume
Page 46 and 47: Figure from Das et al., 2011 showin
Page 48 and 49: Dr. Helen M. Berman Board of Govern
Page 50 and 51: Dr. Chenghua Shao Research Associat
Page 52 and 53: Dr. Joseph Marcotrigiano CABM Resid
Page 54 and 55: The long-term goals of our studies
Page 56 and 57: s Publications: Singarapu, K.K., Mi
Page 58 and 59: Zhao, L., Zhao, K., Hurst, R., Slat
Page 60 and 61: Acton, T.B., Xiao, R., Anderson, S.
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Page 66 and 67: Dr. Ann M. Stock Associate Director
Page 68 and 69: Publications: Barbieri, C.M., Mack,
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Lectures and Seminars 69
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CABM RETREAT, June 30, 2011 Cook Ca
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25 th Anniversary CABM Symposium Fr
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Edery Lab Joseph Albistur George Gh
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PATENTS P. Lobel, et al. “Methods
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Montelione, G.T., Ma, L. and Krug,
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Outside Academic Members Dr. Wayne
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Former CABM Scientific Advisory Boa
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Fiscal Information 86
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Anderson, Stephen Rutgers CABM Gran
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Leukemia & Lymphoma Society BFL-1 a
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Total Award Start - End FY 2011 Dir
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Department of Defense Tumor suppres
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Total Award Start - End FY 2011 Dir
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