p53 represses autophagy in a cell cycle-dependent fashion.
Autophagy is one of the principal mechanisms of cellular defense against nutrient depletion and damage to cytoplasmic organelles. When p53 is inhibited by a pharmacological antagonist (cyclic pifithrin-alpha), depleted by a specific small interfering RNA (siRNA) or deleted by homologous recombination, multiple signs of autophagy are induced. Here, we show by epistatic analysis that p53 inhibition results in a maximum level of autophagy that cannot be further enhanced by a variety of different autophagy inducers including lithium, tunicamycin-induced stress of the endoplasmic reticulum (ER) or inhibition of Bcl-2 and Bcl-X(L) with the BH3 mimetic ABT737. Chemical inducers of autophagy (including rapamycin, lithium, tunicamycin and ABT737) induced rapid depletion of the p53 protein. The absence or the inhibition of p53 caused autophagy mostly in the G(1) phase, less so in the S phase and spares the G(2)/M phase of the cell cycle. The possible pathophysiological implications of these findings are discussed.
Tasdemir
Ezgi
E
INSERM, U848, Villejuif, France.
Maiuri
Maria Chiara
MC
Orhon
Idil
I
Kepp
Oliver
O
Morselli
Eugenia
E
Criollo
Alfredo
A
Kroemer
Guido
G
D001343:Autophagy / Q000235:genetics*; D002453:Cell Cycle; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004843:Epistasis, Genetic; D045325:HCT116 Cells; D006801:Humans; D034741:RNA, Small Interfering / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53