Regulation of autophagy by cytoplasmic p53.
Multiple cellular stressors, including activation of the tumour suppressor p53, can stimulate autophagy. Here we show that deletion, depletion or inhibition of p53 can induce autophagy in human, mouse and nematode cells subjected to knockout, knockdown or pharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels. Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able to repress the enhanced autophagy of p53(-/-) cells. Many different inducers of autophagy (for example, starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediated degradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53 degradation prevented the activation of autophagy in several cell lines, in response to several distinct stimuli. These results provide evidence of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53.
Tasdemir
Ezgi
E
INSERM, U848, France.
Maiuri
M Chiara
MC
Galluzzi
Lorenzo
L
Vitale
Ilio
I
Djavaheri-Mergny
Mojgan
M
D'Amelio
Marcello
M
Criollo
Alfredo
A
Morselli
Eugenia
E
Zhu
Changlian
C
Harper
Francis
F
Nannmark
Ulf
U
Samara
Chrysanthi
C
Pinton
Paolo
P
Vicencio
José Miguel
JM
Carnuccio
Rosa
R
Moll
Ute M
UM
Madeo
Frank
F
Paterlini-Brechot
Patrizia
P
Rizzuto
Rosario
R
Szabadkai
Gyorgy
G
Pierron
Gérard
G
Blomgren
Klas
K
Tavernarakis
Nektarios
N
Codogno
Patrice
P
Cecconi
Francesco
F
Kroemer
Guido
G
D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D016158:Genes, p53; D006801:Humans; D000860:Hypoxia; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D046988:Proteasome Endopeptidase Complex