Multiple endocrine neoplasia type I (MEN1) is a dominantly inherited tumor syndrome characterized by development of tumors in multiple endocrine organs and occasionally in non-endocrine organs. The gene mutated in MEN1 patients, Menl, encodes a protein of 610 amino acid residues, menin. Targeted disruption of Menl in mice also leads to an endocrine tumor syndrome that closely mimics the human MEN1, indicatinga bonafide tumor suppressing function for menin. Since there are no obvious domains in menin that suggest any biochemical functions, it has been challenging yet exciting to elucidate the mechanisms underlyingthe crucial role of menin in tumor suppression. Recently, we have made significant progress in understanding a vital role for menin in TNF-a-mediated apoptosis. We show that menin is essential for optimal TNF-a-induced apoptosis. Moreover, menin directly binds DNA, and two MEN1 disease-related mutants fail to bind DNA. Furthermore, menin plays an essential role in caspase 8 transcription and also binds the promoter of endogenous caspase 8, while two MENl-related meninpoint mutants fail to activate casapse 8 expression and TNF-a-induced apoptosis. Other recent reports show that menin associates with histone methyltransferases that usuallyactivates gene transcription. Together, these results lead us to hypothesize that menin binds to DNAand recruits other transcriptional regulators to the promoter of the caspase 8 gene, resulting in upregulation of caspase 8 transcription and TNF-a-induced apoptosis, as well as suppression of tumorigenesis in MENL Three Specific Aims have been proposed to test these hypotheses. First, we will identify the minimal DNA binding domain in menin and characterize the role of menin-DNA interaction in regulating caspase 8 expression and TNF-a-induced apoptosis. Second, we will examine the role of menin, histone methyltransferases and other menin-interactingproteins in the transcriptional regulation of caspase 8 and TNF-a-induced apoptosis, Third, the role of menin-mediated expression of caspase 8 in suppressing the MEN1 tumorigenesis will be evaluated in classic and conditional Men 1 knock out mice. Results from these independent yet complementary studies will likely significantly advance our understandingof the molecular circuitry of the MEN1 development and shed lights on improvingtherapeutic interventionsfor MEN1 and other related tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA113962-03S1
Application #
7501057
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Ogunbiyi, Peter
Project Start
2005-06-01
Project End
2010-04-30
Budget Start
2007-08-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$46,960
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
Gurung, Buddha; Muhammad, Abdul Bari; Hua, Xianxin (2014) Menin is required for optimal processing of the microRNA let-7a. J Biol Chem 289:9902-8
Gurung, Buddha; Katona, Bryson W; Hua, Xianxin (2014) Menin-mediated regulation of miRNA biogenesis uncovers the IRS2 pathway as a target for regulating pancreatic beta cells. Oncoscience 1:562-6
Thiel, Austin T; Feng, Zijie; Pant, Dhruv K et al. (2013) The trithorax protein partner menin acts in tandem with EZH2 to suppress C/EBP? and differentiation in MLL-AF9 leukemia. Haematologica 98:918-27
Gurung, Buddha; Feng, Zijie; Hua, Xianxin (2013) Menin directly represses Gli1 expression independent of canonical Hedgehog signaling. Mol Cancer Res 11:1215-22
Gurung, Buddha; Hua, Xianxin (2013) Menin/PRMT5/hedgehog signaling: a potential target for the treatment of multiple endocrine neoplasia type 1 tumors. Epigenomics 5:469-71
Gurung, Buddha; Feng, Zijie; Iwamoto, Daniel V et al. (2013) Menin epigenetically represses Hedgehog signaling in MEN1 tumor syndrome. Cancer Res 73:2650-8
Thiel, Austin T; Huang, Jing; Lei, Ming et al. (2012) Menin as a hub controlling mixed lineage leukemia. Bioessays 34:771-80
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
Matkar, Smita S; Durham, Amy; Brice, Angela et al. (2011) Systemic activation of K-ras rapidly induces gastric hyperplasia and metaplasia in mice. Am J Cancer Res 1:432-445
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

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