p53 induces transcriptional and translational programs to suppress cell proliferation and growth

Fabricio Loayza-Puch, Jarno Drost, Koos Rooijers, Rui Lopes, Ran Elkon, Reuven Agami

BACKGROUND: Cell growth and proliferation are tightly connected to ensure that appropriately sized daughter cells are generated following mitosis. Energy stress blocks cell growth and proliferation, a critical response for survival under extreme conditions. Excessive oncogenic stress leads to p53 activation and the induction of senescence, an irreversible state of cell-cycle arrest and a critical component in the suppression of tumorigenesis. Nutrient-sensing and mitogenic cues converge on a major signaling node, which regulates the activity of the mTOR kinase. Although transcriptional responses to energy and oncogenic stresses have been examined by many gene-expression experiments, a global exploration of the modulation of mRNA translation in response to these conditions is lacking. RESULTS: We combine RNA sequencing and ribosomal profiling analyses to systematically delineate modes of transcriptional and translational regulation induced in response to conditions of limited energy, oncogenic stress and cellular transformation. We detect a key role for mTOR and p53 in these distinct physiological states, and provide the first genome-wide demonstration that p53 activation results in mTOR inhibition and a consequent global repression of protein translation. We confirm the role of the direct p53 target genes Sestrin1 and Sestrin2 in this response, as part of the broad modulation of gene expression induced by p53 activation. CONCLUSIONS: We delineate a bimodal tumor-suppressive regulatory program activated by p53, in which cell-cycle arrest is imposed mainly at the transcriptional level, whereas cell growth inhibition is enforced by global repression of the translation machinery.