DRAM, a p53-induced modulator of autophagy, is critical for apoptosis.
Inactivation of cell death is a major step in tumor development, and p53, a tumor suppressor frequently mutated in cancer, is a critical mediator of cell death. While a role for p53 in apoptosis is well established, direct links to other pathways controlling cell death are unknown. Here we describe DRAM (damage-regulated autophagy modulator), a p53 target gene encoding a lysosomal protein that induces macroautophagy, as an effector of p53-mediated death. We show that p53 induces autophagy in a DRAM-dependent manner and, while overexpression of DRAM alone causes minimal cell death, DRAM is essential for p53-mediated apoptosis. Moreover, analysis of DRAM in primary tumors revealed frequent decreased expression often accompanied by retention of wild-type p53. Collectively therefore, these studies not only report a stress-induced regulator of autophagy but also highlight the relationship of DRAM and autophagy to p53 function and damage-induced programmed cell death.
Crighton
Diane
D
Tumour Cell Death Laboratory, Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Wilkinson
Simon
S
O'Prey
Jim
J
Syed
Nelofer
N
Smith
Paul
P
Harrison
Paul R
PR
Gasco
Milena
M
Garrone
Ornella
O
Crook
Tim
T
Ryan
Kevin M
KM
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D001483:Base Sequence; D001665:Binding Sites / Q000502:physiology; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence / Q000502:physiology; D004249:DNA Damage / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C512709:DRAM1 protein, human; D008565:Membrane Proteins; D011506:Proteins; D016159:Tumor Suppressor Protein p53; C018589:lysosomal proteins