D4S234E, a novel p53-responsive gene, induces apoptosis in response to DNA damage.
Understanding intracellular transduction pathways on apoptosis is indispensable for clinical application to develop effective cancer therapies. Transcription factor p53 is activated in response to genotoxic damage and plays crucial roles in apoptosis. p53 regulates the expression of numerous apoptosis-related genes to induce cell death. Here, through genome-wide comprehensive gene expression profile, we identified D4S234E as a novel p53-responsive gene. We determined the p53-binding region in the D4S234E promoter, which is important for p53 regulation in response to DNA damage. Inhibition of D4S234E expression by RNA interference suppressed apoptosis. Furthermore, we observed that D4S234E partially localizes in the endoplasmic reticulum (ER). We found a functional ER retention signal in D4S234E and, more importantly, ER targeting is essential for D4S234E-mediated apoptosis. Finally, depletion of D4S234E diminished genotoxic stress-induced reduction of Bcl-2 and augmentation of CHOP. We thus concluded that a novel p53-responsive gene D4S234E is accumulated in the ER and induces apoptosis in response to DNA damage.
Kudoh
Takuya
T
Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Kimura
Junko
J
Lu
Zheng-Guang
ZG
Miki
Yoshio
Y
Yoshida
Kiyotsugu
K
D017209:Apoptosis / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D015894:Genome, Human; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D002352:Carrier Proteins; C553327:NSG1 protein, human; D009419:Nerve Tissue Proteins; D016159:Tumor Suppressor Protein p53