The phosphatase MKP1 is a transcriptional target of p53 involved in cell cycle regulation.
The tumor suppressor p53 protein suppresses cell growth by inducing cell cycle arrest or apoptosis. Despite the fact that p53-dependent p21-mediated G1 arrest induced by DNA damage is well defined, the role of p53 in the cell cycle in response to the MAKP signaling remains to be determined. Here we show that MKP1, a member of the dual specificity protein phosphatase family capable of inactivating MAPKs, is a transcriptional target of p53. MKP1 mRNA and protein levels were increased upon p53 activation in several well defined p53-regulated cell systems. p53 bound to a consensus p53 binding site located in the second intron of the MKP1 gene and transactivated MKP1 in reporter gene assays. Inhibition of phosphatase activity impaired p53-mediated G1 arrest in arrested human glioblastoma GM cells in response to growth factor stimuli. Importantly conditional expression of MKP1 prevented arrested human cancer cells from entering into the cell cycle. Thus, these results provide a novel mechanism by which p53 controls the cell cycle in response to the MAPK signaling in the absence of DNA damage and suggest that p53 may negatively control the MAKP pathway via MKP1.
Li
Maoxiang
M
Departments of Pathology and Pharmacology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Zhou
Jun-Ying
JY
Ge
Yubin
Y
Matherly
Larry H
LH
Wu
Gen Sheng
GS
D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004249:DNA Damage; D018076:DNA, Complementary / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D005091:Exons; D005434:Flow Cytometry; D016193:G1 Phase; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism / Q000502:physiology*; D007438:Introns; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D010749:Phosphoprotein Phosphatases; D010957:Plasmids / Q000378:metabolism; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D012313:RNA; D008156:Luciferases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases