Multiple endocrine neoplasia, type I (MEN1), is a form of inherited cancer characterized by multiple tumors primarily involving the endocrine glands. The gene for MEN1 is a classic tumor suppressor gene that encodes a nuclear protein called menin. Tumors in affected individuals occur after loss of the wild-type allele, following the classic tumor suppressor model. Although a number of interacting proteins have provided functional insights to menin, it is not clear how the loss of menin causes tumor formation. We recently developed mouse models for MEN1. These mice develop an endocrine tumor spectrum that faithfully recapitulates the corresponding human condition, and therefore are excellent resources to pursue three aims pertaining to the action of the Men1 tumor suppressor gene.
In Specific Aim 1, I will determine the consequence of replacing menin in pancreatic endocrine tumors of Men1 knockout mice.
This aim will be addressed using transgenic mice containing the Men1 gene under the control of an inducible promoter. Although there are several studies suggesting that the reversal of one or more activated oncogenes can cause tumor regression, so far no one has reported the consequences of re-expressing a deleted tumor suppressor gene in cancer.
In Specific Aim 2, 1 will gain insights into how the loss of MEN1, a ubiquitously expressed gene, gives rise to tumors only in a defined set of tissues. To do this, I have engineered mice that are homozygous null for menin in liver, a tissue not normally predisposed to developing tumors in MEN1. Interestingly, Men1-null livers appear entirely normal and remain tumor free throughout adulthood. To gain insights to the paradox of the tissue-specific tumor phenotype in MEN1, I will compare wild-type and Men1-null expression profiles from liver to those generated from endocrine pancreas, a tissue that is susceptible to developing tumors in MEN1. I hypothesize that the identification of genes that show expression differences in Men1-null livers and endocrine pancreas will provide vital clues to tissue specificity in MEN1.
In Specific Aim 3, 1 will take advantage of an approach that couples chromatin immunoprecipitation with microarray technology (ChlP-chip) to identify genes that are transcriptionally co-regulated by menin. Importantly, I present preliminary data in which microarrays containing >18,000 gene promoters were used to identify >50 promoters bound by menin. These results not only illustrate the power and feasibility of this approach, but also provide new mechanistic insights to menin. A comprehensive approach to identify additional genes that are co-regulated by menin will not only increase our understanding of how menin regulates cell proliferation, as studied in Aim 1, but will also nicely complement Aim 2 by providing clues to the paradox of tissue-specific tumor phenotype in MEN1. ? ?
| Schnetz, Michael P; Bartels, Cynthia F; Shastri, Kuntal et al. (2009) Genomic distribution of CHD7 on chromatin tracks H3K4 methylation patterns. Genome Res 19:590-601 |
