Delayed cell cycle progression in selenoprotein W-depleted cells is regulated by a mitogen-activated protein kinase kinase 4-p38/c-Jun NH2-terminal kinase-p53 pathway.
Selenoprotein W (SEPW1) is a ubiquitous, highly conserved thioredoxin-like protein whose depletion causes a transient p53- and p21(Cip1)-dependent G(1)-phase cell cycle arrest in breast and prostate epithelial cells. SEPW1 depletion increases phosphorylation of Ser-33 in p53, which is associated with decreased p53 ubiquitination and stabilization of p53. We report here that delayed cell cycle progression, Ser-33 phosphorylation, and p53 nuclear accumulation from SEPW1 depletion require mitogen-activated protein kinase kinase 4 (MKK4). Silencing MKK4 rescued G(1) arrest, Ser-33 phosphorylation, and nuclear accumulation of p53 induced by SEPW1 depletion, but silencing MKK3, MKK6, or MKK7 did not. SEPW1 silencing did not change the phosphorylation state of MKK4 but increased total MKK4 protein. Silencing p38γ, p38δ, or JNK2 partially rescued G(1) arrest from SEPW1 silencing, suggesting they signal downstream from MKK4. These results imply that SEPW1 silencing increases MKK4, which activates p38γ, p38δ, and JNK2 to phosphorylate p53 on Ser-33 and cause a transient G(1) arrest.
Western Human Nutrition Research Center, United States Department of Agriculture, Agricultural Research Service, University of California, Davis, California 95616, USA. wayne.hawkes@ars.usda.gov
Wayne Chris
WC
Hawkes
Zeynep
Z
Alkan
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D048291:Mitogen-Activated Protein Kinase 12 / Q000235:genetics / Q000378:metabolism*; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D051151:Selenoprotein W / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C495240:SELENOW protein, human; D051151:Selenoprotein W; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13; D048056:Mitogen-Activated Protein Kinase 9; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human