Faculty Collaboration Database

p38 isoforms have opposite effects on AP-1-dependent transcription through regulation of c-Jun. The determinant roles of the isoforms in the p38 MAPK signal specificity. J Biol Chem 2003 Feb 14;278(7):4831-9

Date

12/12/2002

Pubmed ID

12475989

DOI

10.1074/jbc.M207732200

Scopus ID

2-s2.0-0038363324 (requires institutional sign-in at Scopus site)   131 Citations

Abstract

p38 MAPK pathway signaling is known to participate in cell proliferation, apoptosis, and differentiation, in a manner dependent on the cellular context. The factors that determine the specific biological response in a given cell type, however, remain largely unknown. We report opposite effects of the p38 isoforms on regulation of AP-1-dependent activities by p38 activators MAPK kinase 6 (MKK6) and/or arsenite in human breast cancer cells. The p38beta isoform increases the activation of AP-1 transcriptional activities by MKK6 and/or arsenite, whereas p38gamma/p38delta inhibits or has no effect on the stimulation. The p38beta does so by increasing the levels of phosphorylated c-Jun, whereas the p38gamma and -delta isoforms may act by regulating the c-jun transcription. AP-1-dependent processes such as vitamin D receptor gene promoter activation and cellular proliferation were similarly activated by the p38beta or inhibited by the p38gamma and/or -delta isoforms. Whereas the human breast cancer cells express all four isoforms, mouse NIH 3T3 and EMT-6 cells express only some of the p38 family members, with p38beta higher in 3T3 cells but p38delta only detected in the EMT-6 line. Consistent with the positive and negative roles of p38beta and p38delta in AP-1 regulation, MKK6 stimulates AP-1-dependent transcription in NIH 3T3 but not EMT-6 cells. In support of a role of c-Jun regulation by p38 isoforms in determining AP-1 activity, the levels of endogenous c-Jun and its phosphorylated form on p38 activation are higher in NIH 3T3 cells. These results demonstrate the contrasting activities of the different p38 isoforms in transmitting the upstream signal to AP-1 and show that the expression profile of p38 isoforms determines whether the p38 signal pathway activates or inhibits AP-1-dependent processes.

Author List

Pramanik R, Qi X, Borowicz S, Choubey D, Schultz RM, Han J, Chen G

Authors

Guan Chen MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Xiao-Mei Qi MD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

3T3 Cells
Animals
Genes, jun
Humans
Isoenzymes
Mice
Mitogen-Activated Protein Kinases
Signal Transduction
Transcription Factor AP-1
Transcriptional Activation
p38 Mitogen-Activated Protein Kinases