Internal Seminar: Dina Mostafa, Functional Analysis of CCR4-NOT Complex in Pancreatic β-cell Function

Internal Seminar

Speaker: Dina Mostafa, PhD Student, Cell Signal Unit (Tadashi Yamamoto Unit)

Title: Functional Analysis of CCR4-NOT Complex in Pancreatic β-cell Function

Abstract: 

Pancreatic β-cells are responsible for production and secretion of insulin in response to increasing blood glucose levels. Released insulin acts on insulin-sensitive tissues in order to maintain normal glucose homeostasis. Therefore, defects in pancreatic β-cell function lead to hyperglycemia and diabetes mellitus. Posttranscriptional control of gene expression by microRNAs (miRNAs) is crucially important for pancreatic β-cells development, differentiation and function. MicroRNAs control gene expression post-transcriptionally, generally by base pairing to the 3’ untranslated region (3’UTR) of target mRNAs even imperfectly and causing inhibition of their translation as well as deadenylation and destabilization. The carbon catabolite repression 4 (CCR4)–negative on TATA-less (NOT) complex (CCR4-NOT complex), a major deadenylase conserved in eukaryotes, is a key effector of miRNA function, suggesting that the proteins in the CCR4–NOT complex can be important in controlling gene expression in pancreatic β-cells. CNOT3 is a non-catalytic subunit of CCR-NOT4 complex and is a positive modulator of its catalytic function. Knockout of CNOT3 (CNOT3-/-) is embryonically lethal. However, CNOT3+/- mice are viable but lean and show increased insulin sensitivity. Such a reduction of CNOT3 correlates with up-regulation of genes involved in metabolism in these mice. Similar to CNOT3, CNOT7 and CNOT6L, two catalytic subunits of the complex, target energy metabolism related genes. These findings underscore the importance of CCR4-NOT complex in regulating decay of mRNAs important for energy metabolism and supports a possible functional role in pancreatic β-cells. This proposed work will uncover the role of CCR4-NOT complex and the mechanism underlying its function in pancreatic β-cells. This aim will be achieved by generating mutant mice with CNOT3 conditional knockout (cKO) in pancreatic β-cell. Moreover, MIN6, a mouse insulinoma cell line, will be used for mechanistic studies.

Free pizza and soft drinks will be served following the seminar from 5:00 - 5:30 pm. Please join us for refreshments and to continue the scientific discussion!

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