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, Men1, encodes a protein of 610 amino acid residues, menin. Targeted disruption of Men1 in mice also leads to an endocrine tumor syndrome that closely mimics the human MEN1, indicating a bona fide 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 underlying the crucial role of menin in tumor suppression. Recently, we have made significant progress in understanding a vital role for menin in TNF-alpha-mediated apoptosis. We show that menin is essential for optimal TNF-alpha-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 MEN1-related menin point mutants fail to activate caspase 8 expression and TNF-a-induced apoptosis. Other recent reports show that menin associates with histone methyltransferases that usually activates gene transcription. Together, these results lead us to hypothesize that menin binds to DNA and recruits other transcriptional regulators to the promoter of the caspase 8 gene, resulting in upregulation of caspase 8 transcription and TNF-alpha-induced apoptosis, as well as suppression of tumorigenesis in MEN1.
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-alpha-induced apoptosis. Second, we will examine the role of menin, histone methyltransferases and other menin-interacting proteins in the transcriptional regulation of caspase 8 and TNF-alpha-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 understanding of the molecular circuitry of the MEN1 development and shed lights on improving therapeutic interventions for MEN1 and other related tumors.
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