However, the reason for the tissue-specific tumor development in MEN 1 (Multiple Endocrine Neoplasia Syndrome Type 1) remains unclear ( 2). The Menin protein have different roles in transcriptional regulation, DNA damage response, and chromatin maintenance. The MEN1 protein, Menin, is ubiquitously expressed, predominantly localized to the nucleus, and further lacks homology with known proteins ( 1). In conclusion, despite retained Menin expression, proliferation was accelerated, and numerous genes were differentially expressed in the endocrine pancreas of 5-wk-old hz Men1 mice, corroborating the hypothesis that MEN1 is a haploinsufficient suppressor. Lower mRNA was observed for genes involved in growth factor binding. Further, gene ontology analysis showed that genes with higher mRNA expression in the hz endocrine pancreas were associated with e.g. the cytoskeletal regulator myristoylated alanine-rich protein kinase C substrate ( Marcks) was significantly less expressed in hz islets, using in situ proximity ligation assay and Western blotting ( P < 0.001 and P < 0.01, respectively). Some selected genes were studied on the protein level, e.g. The microarray results demonstrated that several genes were differentially expressed. The hz islets show increased proliferation: the Ki-67 index was twice as high as in wt islets (3.48 vs. Array findings were corroborated by quantitative PCR, Western blotting, in situ proximity ligation assay, and immunohistochemistry. Wild-type littermates were used for comparison. Because islet cells of 5-wk-old hz mice express Menin from the retained wt Men1 allele, these were isolated after collagenase digestion of the pancreas, and used for global gene expression array. To study downstream molecular effects of the hz haplotype, a germ line Men1 hz mouse model was used to explore differences in global endocrine pancreatic gene expression. However, endocrine cell proliferation has been observed despite wt allele retention, indicating haploinsufficiency. Individuals carrying heterozygous (hz) MEN1 (Multiple Endocrine Neoplasia Syndrome Type 1) germ line mutations develop endocrine tumors as a result of somatic loss of the wild-type (wt) allele.
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