Proteasome-mediated degradation of Tob is pivotal for triggering UV-induced apoptosis.
Eukaryotic cells respond to genotoxic stress by inducing cell growth arrest or apoptosis. Although the p53 tumor suppressor largely contributes to the response by regulating antiproliferative or pro-apoptotic genes, some genotoxic stresses including ultraviolet (UV) light induce apoptosis even in the absence of p53. The molecular mechanisms by which cells respond to UV in the p53-independent manner remain to be established. Here, we show that UV-induced stress promotes proteasome-dependent degradation of Tob, triggering an apoptotic signal. We found that Tob with either short deletion or a tag sequence at the C terminus was resistant to UV-induced degradation. Introduction of the degradation-resistant Tob impaired UV-induced apoptosis. Reciprocally, suppression of Tob by small interfering RNA (siRNA) resulted in frequent induction of apoptosis irrespective of the presence of functional p53 even at UV doses that do not promote Tob degradation. Finally, tob-deficient (tob(-/-)) mice and primary embryonic fibroblasts (MEFs) from tob(-/-) mice exhibit increased sensitivity to UV irradiation. Thus, proteasomal clearance of Tob provides a novel p53-independent pathway for UV-induced apoptosis.
Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
T
T
Suzuki
J
J
Tsuzuku
K
K
Kawakami
T
T
Miyasaka
T
T
Yamamoto
D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D001973:Bromodeoxyuridine; D019556:COS Cells; D002352:Carrier Proteins / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C098669:TOB1 protein, human; C490903:Tob1 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D046988:Proteasome Endopeptidase Complex; D001973:Bromodeoxyuridine