Control of the autophagy maturation step by the MAPK ERK and p38: lessons from environmental carcinogens.
Macroautophagy (hereafter referred to as autophagy) is the major degradative pathway of long-lived proteins and organelles that fulfils key functions in cell survival, tissue remodeling and tumor suppression. Consistently, alterations in autophagy have been involved in a growing list of pathologies including toxic injury, infections, neurodegeneration, myopathies and cancers. Although critical, the molecular mechanisms that control autophagy remain largely unknown. We have recently exploited the disruption of autophagy by environmental carcinogens as a powerful model to uncover the underlying signaling pathways. Our work published in Cancer Research revealed that the sustained activation of the MAPK ERK pathway by the carcinogen Lindane or the MEK1(+) oncogene alters autophagy selectively at the maturation step resulting in the accumulation of large defective autolysosomes. Consistent with our findings, a similar defect is observed with other common xenobiotics such as dichlorodiphenyltrichloroethane and biphenol A that specifically activate ERK. Conversely, Pentachlorophenol that activates both ERK and p38, fails to induce autophagic vacuolation. In addition, evidence is provided that abrogation of p38 by SB203580 is sufficient to interfere with the normal autophagic maturation step. Altogether, these findings underscore the critical role played by MAPK ERK and p38 in the tight control of the autophagy process at the maturation step.
Corcelle
Elisabeth
E
INSERM U670, IFR 50, Faculté de Médecine, Avenue de Valombrose, 06107 Nice Cedex 2, France.
Djerbi
Nadir
N
Mari
Mireille
M
Nebout
Marielle
M
Fiorini
Céline
C
Fénichel
Patrick
P
Hofman
Paul
P
Poujeol
Philippe
P
Mograbi
Baharia
B
D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology*; D002274:Carcinogens, Environmental / Q000494:pharmacology*; D001556:Hexachlorocyclohexane / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D008954:Models, Biological; D010588:Phagosomes / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D002274:Carcinogens, Environmental; D001556:Hexachlorocyclohexane; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases