My long-term goals are to understand the molecular mechanisms of human hereditary tumor syndromes. Multiple endocrine neoplasia type I (MEN1) is a dominantly inherited disease characterized by development of tumors in multiple endocrine organs. The tumors from the pancreatic islets and intestines have a high malignant potential. The gene mutated in MEN1 patients, tumor suppressor gene menin, has been cloned, but its function in suppressing tumorigenesis is unclear. Thus, a key question is what is the function of menin in suppressing tumorigenesis in MEN1 ? This proposal seeks to address such a question, and it is largely based on our recent findings: (1) Menin associates with chromatin and nuclear matrix; (2) Menin interacts with FANCD2, a gene involved in DNA repair, and the menin -/-cells are hypersensitive to DNA damage; (3) Menin induces a Bax/Bak-dependent apoptotic pathway. We hypothesize that menin regulates gene transcription by associating with chromatin and nuclear matrix, participates in DNA repair in concert with FANCD2, and control a DNA damage-induced apoptotic pathway. Thus, the goals of this proposal are to characterize the roles of menin in regulating gene transcription, DNA repair, and apoptosis. To test these hypotheses, first, we will identify domains of menin that mediate association with chromatin or the nuclear matrix and analyze their role in regulation of gene transcription. Second, we will characterize the roles of menin in DNA repair in concert with FANCD2 in cultured ceils and in a mouse model. Third, the relevance of menin-mediated apoptosis to MEN1 and menin-regulated steps of apoptosis will be investigated. Information generated from these independent yet complementary studies will likely significantly advance our understanding of the molecular pathogenesis of MEN 1 and shed lights on improving therapeutic interventions for MEN1.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100912-02
Application #
6849231
Study Section
Pathology B Study Section (PTHB)
Program Officer
Okano, Paul
Project Start
2004-02-03
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$287,592
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zhang, Hui; Liu, Zu-Guo; Hua, Xian-Xin (2011) Menin expression is regulated by transforming growth factor beta signaling in leukemia cells. Chin Med J (Engl) 124:1556-62
Wu, Ting; Zhang, Xiuli; Huang, Xiaohua et al. (2010) Regulation of cyclin B2 expression and cell cycle G2/m transition by menin. J Biol Chem 285:18291-300
Thiel, Austin T; Blessington, Peter; Zou, Tao et al. (2010) MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer Cell 17:148-59
Gao, S-B; Feng, Z-J; Xu, B et al. (2009) Suppression of lung adenocarcinoma through menin and polycomb gene-mediated repression of growth factor pleiotrophin. Oncogene 28:4095-104
Maillard, Ivan; Chen, Ya-Xiong; Friedman, Ann et al. (2009) Menin regulates the function of hematopoietic stem cells and lymphoid progenitors. Blood 113:1661-9
Yan, J; Yang, Y; Zhang, H et al. (2009) Menin interacts with IQGAP1 to enhance intercellular adhesion of beta-cells. Oncogene 28:973-82
Wu, Xinjiang; Hua, Xianxin (2008) Menin, histone h3 methyltransferases, and regulation of cell proliferation: current knowledge and perspective. Curr Mol Med 8:805-15
La, Ping; Yang, Yuqing; Karnik, Satyajit K et al. (2007) Menin-mediated caspase 8 expression in suppressing multiple endocrine neoplasia type 1. J Biol Chem 282:31332-40
Yang, Yuqing; Hua, Xianxin (2007) In search of tumor suppressing functions of menin. Mol Cell Endocrinol 265-266:34-41
La, P; Desmond, A; Hou, Z et al. (2006) Tumor suppressor menin: the essential role of nuclear localization signal domains in coordinating gene expression. Oncogene 25:3537-46

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