Mitogen-activated protein kinase phosphatase 2: a novel transcription target of p53 in apoptosis.
The p53 tumor suppressor plays critical roles in diverse cellular responses such as cell cycle arrest, senescence, and apoptosis through transcriptional control of its target genes. Identification and characterization of new p53 target genes will advance our understanding of how p53 exerts its multiple regulatory functions. In this article, we show that mitogen-activated protein kinase phosphatase 2 (MKP2) is a novel transcription target of p53 in mediating apoptosis. Moreover, we identify a 10-bp perfect palindrome motif (CTGGCGCCAG) in the MKP2 promoter as a new binding site for p53 to activate the MKP2 gene. This GC-rich palindrome is completely different from the consensus p53 binding sequence. Induction of MKP2 is highly responsive to oxidative stress in a p53-dependent manner. Interestingly, the p53-dependent induction of MKP2 is prominent only in the cellular response to stimuli leading to apoptosis but not to cell cycle arrest. In response to oxidative stress, MKP2 is not only required for p53-mediated apoptosis, but ectopic MKP2 expression can also enhance apoptotic responses even independent of p53. These data suggest that p53 regulates distinct genes via different binding mechanisms and that MKP2 is an essential target of p53 in signaling apoptosis.
Shen
Wen Hong
WH
Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Wang
Jianli
J
Wu
Jingjing
J
Zhurkin
Victor B
VB
Yin
Yuxin
Y
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics; D054637:Dual-Specificity Phosphatases; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D054639:Mitogen-Activated Protein Kinase Phosphatases; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054648:Protein Phosphatase 2; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases