Defective autophagy control by the p53 rheostat in cancer.
Autophagy is a finely regulated, lysosomal catabolic pathway that contributes to the turnover of long-lived proteins and to the elimination of old/damaged organelles. Autophagy exerts bona fide oncosuppressive functions by: (1) limiting chromosomal instability; (2) reducing potentially mutagenic oxidative stress; and (3) restraining intratumoral necrosis and local inflammation. Defective autophagy constitutes a hallmark of cancer cells together with: (1) provision of autonomous growth signals;, (2) insensitivity to antiproliferative stimuli; (3) disabled apoptosis; (4) limitless replication; (5) production of angiogenic factors; (6) tissue invasion with metastasis; (7) avoidance of the immune response; and (8) enhanced anabolism. p53 is the best-known human oncosuppressor protein, and its genetic/epigenetic inactivation has been observed in more than 50% of all human cancers. p53 mostly mediates tumor suppression by transactivating pro-apoptotic and cell cycle arresting genes, but also by favoring mitochondrial apoptosis in a transcription-independent fashion, by modulating metabolic circuitries and by regulating autophagy. p53 mutations (or epigenetic changes) that simultaneously abolish its pro-apoptotic and autophagy-inhibitory functions behave as "multi-hit" events, as opposed to "single-hit" mutations that only affect the classical (pro-apoptotic and/or cell cycle-arresting) functions of the p53 system. We speculate that, in this latter case, additional genetic/epigenetic events resulting in disabled autophagy are likely to contribute to accelerated oncogenesis.
Galluzzi
Lorenzo
L
INSERM, U848, Institut Gustave Roussy, and Université Paris Sud-XI, Villejuif, France.
Morselli
Eugenia
E
Kepp
Oliver
O
Maiuri
Maria Chiara
MC
Kroemer
Guido
G
D051017:Apoptosis Regulatory Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D001343:Autophagy; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins; D009369:Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C512709:DRAM1 protein, human; C576324:ATM protein, human; C512708:TIGAR protein, human