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Yap1 plays a protective role in suppressing free fatty acid-induced apoptosis and promoting beta-cell survival.

ABSTRACT: Mammalian pancreatic ?-cells play a pivotal role in development and glucose homeostasis through the production and secretion of insulin. Functional failure or decrease in ?-cell number leads to type 2 diabetes (T2D). Despite the physiological importance of ?-cells, the viability of ?-cells is often challenged mainly due to its poor ability to adapt to their changing microenvironment. One of the factors that negatively affect ?-cell viability is high concentration of free fatty acids (FFAs) such as palmitate. In this work, we demonstrated that Yes-associated protein (Yap1) is activated when ?-cells are treated with palmitate. Our loss- and gain-of-function analyses using rodent insulinoma cell lines revealed that Yap1 suppresses palmitate-induced apoptosis in ?-cells without regulating their proliferation. We also found that upon palmitate treatment, re-arrangement of F-actin mediates Yap1 activation. Palmitate treatment increases expression of one of the Yap1 target genes, connective tissue growth factor (CTGF). Our gain-of-function analysis with CTGF suggests CTGF may be the downstream factor of Yap1 in the protective mechanism against FFA-induced apoptosis.

SUBMITTER: Deng Y

PROVIDER: S-EPMC4853318 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Yap1 plays a protective role in suppressing free fatty acid-induced apoptosis and promoting beta-cell survival.

Deng Yaoting Y Matsui Yurika Y Pan Wenfei W Li Qiu Q Lai Zhi-Chun ZC

Protein & cell 20160322 5

Mammalian pancreatic β-cells play a pivotal role in development and glucose homeostasis through the production and secretion of insulin. Functional failure or decrease in β-cell number leads to type 2 diabetes (T2D). Despite the physiological importance of β-cells, the viability of β-cells is often challenged mainly due to its poor ability to adapt to their changing microenvironment. One of the factors that negatively affect β-cell viability is high concentration of free fatty acids (FFAs) such ...[more]

PMID: 27000077

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Project description:BACKGROUND:The most life-threatening step during malignant tumor progression is reached when cancer cells leave the primary tumor mass and seed metastasis in distant organs. To infiltrate the surrounding tissue and disseminate throughout the body, single motile tumor cells leave the tumor mass by breaking down cell-cell contacts in a process called epithelial to mesenchymal transition (EMT). An EMT is a complex molecular and cellular program enabling epithelial cells to abandon their differentiated phenotype, including cell-cell adhesion and cell polarity, and to acquire mesenchymal features and invasive properties. METHODS:We employed gene expression profiling and functional experiments to study transcriptional control of transforming growth factor (TGF)?-induced EMT in normal murine mammary gland epithelial (NMuMG) cells. RESULTS:We identified that expression of the transcription factor forkhead box protein F2 (Foxf2) is upregulated during the EMT process. Although it is not required to gain mesenchymal markers, Foxf2 is essential for the disruption of cell junctions and the downregulation of epithelial markers in NMuMG cells treated with TGF?. Foxf2 is critical for the downregulation of E-cadherin by promoting the expression of the transcriptional repressors of E-cadherin, Zeb1 and Zeb2, while repressing expression of the epithelial maintenance factor Id2 and miRNA 200 family members. Moreover, Foxf2 is required for TGF?-mediated apoptosis during EMT by the transcriptional activation of the proapoptotic BH3-only protein Noxa and by the negative regulation of epidermal growth factor receptor (EGFR)-mediated survival signaling through direct repression of its ligands betacellulin and amphiregulin. The dual function of Foxf2 during EMT is underscored by the finding that high Foxf2 expression correlates with good prognosis in patients with early noninvasive stages of breast cancer, but with poor prognosis in advanced breast cancer. CONCLUSIONS:Our data identify the transcription factor Foxf2 as one of the important regulators of EMT, displaying a dual function in promoting tumor cell apoptosis as well as tumor cell migration.

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Yap1 plays a protective role in suppressing free fatty acid-induced apoptosis and promoting beta-cell survival.

Publications

Yap1 plays a protective role in suppressing free fatty acid-induced apoptosis and promoting beta-cell survival.

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