Research Interests
1) The critical role of the tumor suppressor, Menin, in epigenetic regulation of gene transcription, cell signaling, cell proliferation, and the underlying mechanisms; suppression of neuroendocrine/carcinoid tumors by targeting menin-regulated pathways
2) The interplay of Menin, MLL methyltransferase, and oncogenic MLL fusion proteins in promoting leukemogenesis
3) Reversal of diabetes by inhibiting menin
4) Signal transduction mediated by transforming growth factor beta (TGF-ß) and menin.
Key words: Menin, Men1, epigenetics, MLL, histone methyltransferase, leukemia, neuroendocrine tumors, diabetes, and TGF-ß signaling.
Description of Research
Our research focuses on elucidating the molecular mechanisms whereby menin-mediated epigenetic mechanisms in regulating endocrine cells including pancreatic beta cells, endocrine tumors, and MLL fusion protein-induced leukemia. In particular, we are interested in dissecting the function of menin, which is mutated in hereditary human tumor syndrome, Multiple Endocrine Neoplasia Type 1 (MEN1), in repressing beta cells and endocrine tumors and in promoting leukemogenesis.
1. We seek to elucidate how Menin suppresses endocrine cells, such as pancreatic beta cells, via regulating histone methylations and expression of pro-proliferative genes. We are also interested in identifying menin-regulated key pathways that can be suppressed to inhibit neuroendocrine tumors.
2. Determining how menin, which acts as a tumor promoter in MLL fusion protein-induced leukemia, cooperates with wild-type MLL protein to promote leukemia and how the menin and wt MLL axis can be suppressed to improve therapy for this aggressive leukemia.
3. Understanding how inhibition of menin leads to reversal of established diabetes in mouse models and determining whether the menin pathway could be explored to ameliorate diabetes.
4. Investigating the interplay between menin, post-transcriptional modifications of menin, and TGF-ß signaling in repressing pancreatic beta cells. As both menin and TGF-ß inhibit cell proliferation, we will test whether menin and TGF-ß cooperate to suppress beta cell proliferation and the underlying mechanisms, using biochemical studies and mouse models.
These comprehensive approaches will provide novel insights into the molecular mechanisms for MEN1 tumorigenesis, regulation of beta cells, and leukemogenesis, shedding light on improving therapy against neuroendocrine tumors, leukemia, and diabetes.
Rotation Projects for 2010-2011
1. To identify potentially functional post-translational modifications of menin
2. To investigate how Men1 excision de-represses multiple pro-proliferative genes and upregulates beta cell proliferation
3. To identify functional and epigenetic partners of menin that control leukemogenesis or neuroendocrine tumors.
Lab personnel:
Zijie Feng, Visiting Graduate Student
Buddha Gurung, Postdoctoral Researcher
Daniel Iwamoto, Research Specialist and Lab Manager
Louise Li, Undergraduate Student
Jennifer Liao, Undergraduate Student
Smita Matkar, Postdoctoral Researcher
Abdul Bari Muhammad, Postdoctoral Researcher
Erin Quinn, Administrative Coordinator
Austin Thiel, Graduate Student
Selected Publications
Huang J, Gurung B, Wan B, Matkar S, Veniaminova NA, Wan K, Merchant JL, Hua X, Lei M.: The same pocket in menin binds both MLL and JUND but has opposite effects on transcription.
Nature 482(7386): 542-6, February 2012.
Thiel AT, Blessington P, Zou T, Feather D, Wu X, Yan J, Zhang H, Liu Z, Ernst P, Koretzky GA, Hua X.: MLL-AF9-Induced Leukemogenesis Requires Coexpression of the Wild-Type Mll Allele. Cancer Cell 17(2): 148-159, Feb 2010.
Yang Yuqing, Gurung Buddha, Wu Ting, Wang Haoren, Stoffers Doris A, Hua Xianxin: Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene. Proceedings of the National Academy of Sciences of the United States of America 107(47): 20358-63, Nov 2010.
Wu Ting, Zhang Xiuli, Huang Xiaohua, Yang Yuqing, Hua Xianxin: Regulation of cyclin B2 expression and cell cycle G2/m transition by menin. The Journal of Biological Chemistry 285(24): 18291-300, Jun 2010.
Aggarwal Priya, Vaites Laura Pontano, Kim Jong Kyong, Mellert Hestia, Gurung Buddha, Nakagawa Hiroshi, Herlyn Meenhard, Hua Xianxin, Rustgi Anil K, McMahon Steven B, Diehl J Alan: Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase. Cancer cell 18(4): 329-40, Oct 2010.
Yan J, Yang Y, Zhang H, King C, Kan H-M, Cai Y, Yuan C-X, Bloom G S, Hua X: Menin interacts with IQGAP1 to enhance intercellular adhesion of beta-cells. Oncogene 28(7): 973-82, Feb 2009.
Maillard Ivan, Chen Ya-Xiong, Friedman Ann, Yang Yuqing, Tubbs Anthony T, Shestova Olga, Pear Warren S, Hua Xianxin: Menin regulates the function of hematopoietic stem cells and lymphoid progenitors. Blood 113(8): 1661-9, Feb 2009.
Wu Xinjiang, Hua Xianxin: Menin, histone h3 methyltransferases, and regulation of cell proliferation: current knowledge and perspective. Current Molecular Medicine 8(8): 805-15, Dec 2008.
Yang Yuqing, Hua Xianxin: In search of tumor suppressing functions of menin. Molecular and Cellular Endocrinology 265-266: 34-41, Feb 2007.
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Last updated: 09/13/2012
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