Abstract
In recent years the tumor suppressor p53 has been increasingly recognized as a potent regulator of the cell metabolism and for its ability to inhibit the critical pro-survival kinases AKT and mTOR. The mechanisms through which p53 controls AKT and mTOR, however, are largely unclear. Here, we demonstrate that p53 activates the metabolic regulator DDIT4 indirectly through the regulatory factor X 7 (RFX7). We provide evidence that DDIT4 is required for p53 to inhibit mTOR complex 2 (mTORC2)-dependent AKT activation. Most strikingly, we also find that the DDIT4 regulator RFX7 is required for p53-mediated inhibition of mTORC1 and AKT. Our results suggest that AMPK activation plays no role and p53-mediated AKT inhibition is not critical for p53-mediated mTORC1 inhibition. Moreover, using recently developed physiological cell culture media we uncover that basal p53 and RFX7 activity can play a critical role in restricting mTORC1 activity under physiological nutrient conditions, and we propose a nutrient-dependent model for p53-RFX7-mediated mTORC1 inhibition. These results establish RFX7 and its downstream target DDIT4 as essential effectors in metabolic control elicited by p53.
Highlights
The pro-survival kinase mTOR supports tumor development and is frequently activated in cancer [1]
While many components and regulators of the PI3K-AKT-mTORC1 and AMPK-mTORC1 signaling pathways are regulated by p53 on mRNA level, only a few proteins were shown so far to play a role in p53-mediated AKT and mTORC1 inhibition
Our findings show regulatory factor X 7 (RFX7) to be a regulator of AKT and mTORC1 activity both downstream and independent of p53
Summary
The pro-survival kinase mTOR (mammalian target of rapamycin) supports tumor development and is frequently activated in cancer [1]. The mTOR kinase is the catalytic subunit of two distinct complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2), and pro-survival properties are largely attributed to mTORC1. The bestdescribed signaling pathway inducing mTORC1 involves the triggering of PI3K (phosphatidylinositol-4,5-bisphosphate 3kinase) by growth factors and other external stimuli. The protein kinase AKT ( known as protein kinase B; PKB) is activated through phosphorylation at Thr308 and Ser473 by PDK1 (pyruvate dehydrogenase kinase 1) and mTORC2, respectively [2]. AKT phosphorylates and deactivates the mTORC1 inhibitors TSC2 and PRAS40, leading to mTORC1 activation [1, 2]. While PI3K-AKT-signaling activates mTORC1 in response to growth stimuli, AMPK (adenosine monophosphate-activated protein kinase) senses energy levels and inhibits mTORC1 when energy supply is low. PI3K-AKT-mTORC1 and AMPK-mTORC1 are two major signaling pathways regulating mTORC1 in response to growth factors and energy levels, respectively
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