ZNF768 links oncogenic RAS to cellular senescence.

RAS proteins are GTPases that lie upstream of a signaling network impacting cell fate determination. How cells integrate RAS activity to balance proliferation and cellular senescence is still incompletely characterized. Here, we identify ZNF768 as a phosphoprotein destabilized upon RAS activation. We report that ZNF768 depletion impairs proliferation and induces senescence by modulating the expression of key cell cycle effectors and established p53 targets. ZNF768 levels decrease in response to replicative-, stress- and oncogene-induced senescence. Interestingly, ZNF768 overexpression contributes to bypass RAS-induced senescence by repressing the p53 pathway. Furthermore, we show that ZNF768 interacts with and represses p53 phosphorylation and activity. Cancer genomics and immunohistochemical analyses reveal that ZNF768 is often amplified and/or overexpressed in tumors, suggesting that cells could use ZNF768 to bypass senescence, sustain proliferation and promote malignant transformation. Thus, we identify ZNF768 as a protein linking oncogenic signaling to the control of cell fate decision and proliferation.

In vivo measurement of energy substrate contribution to cold-induced brown adipose tissue thermogenesis.

The present study was designed to investigate the effects of cold on brown adipose tissue (BAT) energy substrate utilization in vivo using the positron emission tomography tracers [(18)F]fluorodeoxyglucose (glucose uptake), 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid [nonesterified fatty acid (NEFA) uptake], and [(11)C]acetate (oxidative activity). The measurements were performed in rats adapted to 27°C, which were acutely subjected to cold (10°C) for 2 and 6 hours, and in rats chronically adapted to 10°C for 21 days, which were returned to 27°C for 2 and 6 hours. Cold exposure (acutely and chronically) led to increases in BAT oxidative activity, which was accompanied by concomitant increases in glucose and NEFA uptake. The increases were particularly high in cold-adapted rats and largely readily reduced by the return to a warm environment. The cold-induced increase in oxidative activity was meaningfully blunted by nicotinic acid, a lipolysis inhibitor, which emphasizes in vivo the key role of intracellular lipid in BAT thermogenesis. The changes in BAT oxidative activity and glucose and NEFA uptakes were paralleled by inductions of genes involved in not only oxidative metabolism but also in energy substrate replenishment (triglyceride and glycogen synthesis). The capacity of BAT for energy substrate replenishment is remarkable.

Myeloid-specific Rictor deletion induces M1 macrophage polarization and potentiates in vivo pro-inflammatory response to lipopolysaccharide.

The phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) axis plays a central role in attenuating inflammation upon macrophage stimulation with toll-like receptor (TLR) ligands. The mechanistic target of rapamycin complex 2 (mTORC2) relays signal from PI3K to Akt but its role in modulating inflammation in vivo has never been investigated. To evaluate the role of mTORC2 in the regulation of inflammation in vivo, we have generated a mouse model lacking Rictor, an essential mTORC2 component, in myeloid cells. Primary macrophages isolated from myeloid-specific Rictor null mice exhibited an exaggerated response to TLRs ligands, and expressed high levels of M1 genes and lower levels of M2 markers. To determine whether the loss of Rictor similarly affected inflammation in vivo, mice were either fed a high fat diet, a situation promoting chronic but low-grade inflammation, or were injected with lipopolysaccharide (LPS), which mimics an acute, severe septic inflammatory condition. Although high fat feeding contributed to promote obesity, inflammation, macrophage infiltration in adipose tissue and systemic insulin resistance, we did not observe a significant impact of Rictor loss on these parameters. However, mice lacking Rictor exhibited a higher sensitivity to septic shock when injected with LPS. Altogether, these results indicate that mTORC2 is a key negative regulator of macrophages TLR signalling and that its role in modulating inflammation is particularly important in the context of severe inflammatory challenges. These observations suggest that approaches aimed at modulating mTORC2 activity may represent a possible therapeutic approach for diseases linked to excessive inflammation.

Connecting mTORC1 signaling to SREBP-1 activation.

PURPOSE OF REVIEW: The implication of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) in promoting protein synthesis has been well described. Over the past years, several studies revealed that mTORC1 also plays a crucial role in promoting lipid biosynthesis and that such connection could be linked to diseases including obesity, nonalcoholic fatty liver disease (NAFLD), and cancer. Here, we review the mechanisms by which mTORC1 regulates lipid synthesis by focusing on the key signaling events that trigger hepatic de-novo lipogenesis in response to nutrients and insulin. RECENT FINDINGS: mTORC1 promotes lipid synthesis by activating the transcription factor sterol regulatory element binding protein 1 (SREBP-1). Recent studies indicate that mTORC1 regulates SREBP-1 activation at multiple levels. Although mTORC1 was originally shown to be necessary and sufficient to activate SREBP-1 in vitro, new studies indicate that hyperactivation of mTORC1 is insufficient to trigger SREBP-1 activation and lipid biogenesis in vivo. These findings reveal that the molecular connection between mTORC1 and SREBP-1 is more complex than originally envisioned. SUMMARY: The discovery of a connection between mTORC1 and SREBP-1 opens a new chapter in our understanding of the molecular mechanisms regulating de-novo lipogenesis. A better comprehension of these mechanisms is key for the development of new tools to treat NAFLD and its complications.