mTORC1 signaling and regulation of pancreatic β-cell mass
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...As such, Akt isoforms play key roles in cell survival [17], proliferation [21], growth [22], migration [23], polarity [24], insulin-evoked...
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...Intriguingly, in HEK293T cells, the ISR preferentially reduces translation of MTOR-regulated genes (61); β cell proliferation is strictly dependent on MTOR activation (62)....
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...The oxidative stress can activate a series of stress pathways involving a family of serine/threonine kinases including AKT, which in turn have a negative effect on insulin signaling [21]....
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"mTORC1 signaling and regulation of ..." refers background in this paper
...(2) Inhibition of β-cell proliferation by rapamycin results from including both AMPK-dependent and independent pathways....
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...mTORC1 controls growth (cell size), proliferation (cell number) and metabolism directly, by modulating eukaryotic initiation factor 4E-binding proteins (4E-BP 1, 2 and 3) and ribosomal protein S6 kinases (S6K 1 and 2), and indirectly, by attenuating AKT signaling via an mTORC1/ S6K-mediated negative feedback loop.(1-10) How TSC/mTOR signaling regulates β-cell mass expansion is not completely understood....
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...This effect is mediated by an S6K1-dependent negative feedback loop resulting in phosphorylation and degradation of IRS1.(1-4) Until recently, most of the evidence supporting the role of mTORC1 in insulin-sensitive tissues was derived from the use of rapamycin and alterations in insulin sensitivity in global S6K and 4E-bp-deficient mice....
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...45 However, chronic activation of S6K negatively regulates IRS1, therefore inactivating the PI3K/AKT signaling pathway.1-4,47 Phosphorylation of the 4E-BPs triggers the release of eIF4E, initiating cap-dependent translation.48,49 This arm of mTORC1 signaling has been linked to induction of cell proliferation independent of the mTORC1-S6K1 arm.50 Together these substrates downstream of mTORC1 play an integral role in mRNA translation initiation and progression, thus controlling the rate of protein synthesis....
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...One consequence of chronic mTORC1 hyperactivation is the induction of an S6K1-dependent negative feedback loop, leading to attenuation of AKT signaling in multiple tissues and insulin resistance.(1-4) It has been proposed that in contrast to classic feedback loops, where a threshold is reached before inhibition occurs, mTORC1 seems to suppress growth factor signaling in a more gradual and continual fashion....
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