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-β signaling in repressing pancreatic beta cells. As both menin and TGF-β inhibit cell proliferation, we will test whether menin and TGF-β 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.
The Hua Laboratory
The research team of Xianxin Hua, Ph.D., seeks to understand how epigenetic regulations, especially those mediated by menin, control development of a variety of diseases, such as endocrine tumors, leukemia, and diabetes. His group has discovered that menin may act as a scaffold protein or a node to interact with various epigenetic regulators to control expression of genes that modulate cell proliferation and survival. They are elucidating how a cascade of the menin-mediated regulatory step is controlled at the molecular level, using a variety of approaches involving molecular and cell biology, genetics, and mouse models. They seek to help improve the treatment of the diseases by targeting the novel molecular steps.
01.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.
02. 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.
03. Yang Y, Gurung B, Wu T, Wang H, Stoffers DA, Hua X. Reversal of pre-existing hyperglycemia in diabetic mice by acute deletion of the Men1 gene. Proceedings of the National Academy of Sciences USA. Epub ahead of print Nov. 8, 2010.
04. Wu T, Zhang X, Huang X, Yang Y, Hua X. Regulation of cyclin B2 expression and G2/M transition by menin. Journal of Biological Chemistry. Jun 11;285(24):18291-300. 2010.
05. Feng ZJ, Gao SB, Wu Y, Xu X-F, Hua X, Jin G-H. Lung cancer cell migration is regulated via repressing growth factor PTN/ RPTP ß/? signaling by menin. Oncogene. (29) 5416-5426. 2010.
06. Yan J, Yang Y, Zhang H, King C, Kan H-M, Cai Y, Yuan C-X, Bloom GS, Hua X. Menin interacts with IQGAP1 to enhance intercellular adhesion of beta-cells. Oncogene. 28(7): 973-82, Feb 2009.
07. Maillard I, Chen Y-X, Friedman A, Yang Y, Tubbs AT, Shestova O, Pear WS, Hua X. Menin regulates the function of hematopoietic stem cells and lymphoid progenitors. Blood. 113(8): 1661-9, Feb 2009.
08. Wu X, Hua X. Menin, histone h3 methyltransferases, and regulation of cell proliferation: current knowledge and perspective. Current Molecular Medicine. 8(8): 805-15, Dec 2008.
09. La P, Yang Y, Karnik SK, Silva AC, Schnepp RW, Kim SK, Hua X. Menin-mediated caspase 8 expression in suppressing multiple endocrine neoplasia type 1. Journal of Biological Chemistry 282(43): 31332-40, Oct 2007.
10. Yang Y, Hua X. In search of tumor suppressing functions of menin. Molecular and Cellular Endocrinology. 265-266: 34-41, Jan 2007.
Ashley Banks - Administrative Assistant
Austin Thiel - Graduate Student
Buddha Gurung - Postdoctoral Researcher
Daniel Iwamoto - Research Specialist and Lab Manager
Jennifer Liao - Undergraduate Student
Louise Li - Undergraduate Student
Smita Matkar - Postdoctoral Researcher
Yuqing Yang - Postdoctoral Researcher
Zijie Feng - Visiting Graduate Student
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