Project description:Pancreatic ß-cells adapt to compensate for the increased metabolic demand during insulin resistance. While the microRNA pathway has an essential role in the expansion of ß-cell mass, the extent of its contribution is unclear. Here we show that miR-184 is silenced in the pancreatic islets of several insulin-resistant mouse models and in the islets of type-2 diabetic human subjects. Reduction of miR-184 promotes the expression of its target Argonaute2 (Ago2), a component of the microRNA-induced silencing complex. While over-expression of Ago2 increased ß-cell proliferation, conditional deletion decreased ß-cell number. Moreover, restored expression of miR-184 in leptin-deficient ob/ob mice decreased Ago2 and prevented compensatory ß-cell expansion. Loss of Ago2 expression during insulin resistance blocked ß-cell growth and relieved the regulation of miR-375-targeted genes including the growth suppressor Cadm1. This study identifies the regulation of Ago2 by miR-184 as an essential component of the compensatory response to promote proliferation during insulin resistance.
Project description:Pancreatic M-CM-^_-cells adapt to compensate for the increased metabolic demand during insulin resistance. While the microRNA pathway has an essential role in the expansion of M-CM-^_-cell mass, the extent of its contribution is unclear. Here we show that miR-184 is silenced in the pancreatic islets of several insulin-resistant mouse models and in the islets of type-2 diabetic human subjects. Reduction of miR-184 promotes the expression of its target Argonaute2 (Ago2), a component of the microRNA-induced silencing complex. While over-expression of Ago2 increased M-CM-^_-cell proliferation, conditional deletion decreased M-CM-^_-cell number. Moreover, restored expression of miR-184 in leptin-deficient ob/ob mice decreased Ago2 and prevented compensatory M-CM-^_-cell expansion. Loss of Ago2 expression during insulin resistance blocked M-CM-^_-cell growth and relieved the regulation of miR-375-targeted genes including the growth suppressor Cadm1. This study identifies the regulation of Ago2 by miR-184 as an essential component of the compensatory response to promote proliferation during insulin resistance. MIN6 cells were transfected with Doxycyline responsive plasmids including the tetO-184 construct in biological triplicates for every time point. The conditions included untransfected control (CTR, induced), Transfected Control (TC, uninduced) along the time points of miR-184 overexpression in 16, 24, 48, and 72 hours of doxycycline treatment.
Project description:We found that BAP1 (BRCA1 Associated Protein-1) shows loss of heterozygosity in over 25% of pancreatic cancer patients and functions as tumor suppressor. Conditional deletion of Bap1 in murine pancreas led to genomic instability, accumulation of DNA damage, and an inflammatory response that evolved to pancreatitis with full penetrance. Concomitant expression of oncogenic KrasG12D led to malignant transformation and development of invasive and metastatic pancreatic cancer. At the molecular level, BAP1 maintains the integrity of the exocrine pancreas by regulating genomic stability and its loss confers sensitivity to radio- and platinum-based therapies.
