Abstract
The tumor suppressor p53 is activated upon multiple cellular stresses, including DNA damage, oncogene activation, ribosomal stress, and hypoxia, to induce cell cycle arrest, apoptosis, and senescence. Mammalian target of rapamycin (mTOR), an evolutionarily conserved serine/threonine protein kinase, serves as a central regulator of cell growth, proliferation, and survival by coordinating nutrients, energy, growth factors, and oxygen levels. p53 dysfunction and mTOR pathway hyperactivation are hallmarks of human cancer. The balance between response to stresses or commitment to cell proliferation and survival is governed by various regulatory loops between the p53 and mTOR pathways. In this review, we first briefly introduce the tumor suppressor p53 and then describe the upstream regulators and downstream effectors of the mTOR pathway. Next, we discuss the role of p53 in regulating the mTOR pathway through its transcriptional and non-transcriptional effects. We further describe the complicated role of the mTOR pathway in modulating p53 activity. Finally, we discuss the current knowledge and future perspectives on the coordinated regulation of the p53 and mTOR pathways.
Highlights
THE TUMOR SUPPRESSOR P53p53, a well-known tumor suppressor, acts as a “guardian of the genome” to maintain genome stability and cellular homeostasis (Vousden and Prives, 2009; Hafner et al, 2019)
We summarize the current knowledge regarding the role of p53 in the regulation of the Mammalian target of rapamycin (mTOR) pathway through transcriptiondependent and transcription-independent mechanisms
The coordinated regulation of the tumor suppressor p53 and the mTOR pathway is critical for cells and organisms to maintain homeostasis in response to various stimuli. p53 controls the mTOR pathway at multiple levels: 1) p53 directly regulates several signaling mechanisms in the mTOR pathway; 2) miRNAs, downstream of p53, regulate the mTOR pathway at the posttranscriptional level; 3) cytoplasmic p53 may control the AMPKmTOR axis to inhibit autophagy by protein-protein interaction
Summary
P53, a well-known tumor suppressor, acts as a “guardian of the genome” to maintain genome stability and cellular homeostasis (Vousden and Prives, 2009; Hafner et al, 2019). P53 exerts tumor-suppressive effects by directly binding to specific DNA sequences to activate or repress the transcription of target genes, such as MDM2 (Barak et al, 1993), p21 (elDeiry et al, 1993), NOXA (Oda et al, 2000), PUMA (Nakano and Vousden, 2001), and RPS27L (He and Sun, 2007; Li et al, 2007) [for review, see (Fischer, 2017)]. Accumulating evidence indicates that the tumor suppressor p53 regulates the machinery of the mTOR pathway at multiple levels to control a broad array of cellular processes, including cell proliferation, apoptosis, autophagy, migration, and tumorigenesis. A thorough understanding of the interplay between p53 and the mTOR pathway will shed light on the development of novel strategies for cancer therapy
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