Dehydroepiandrosterone negatively regulates the p38 mitogen-activated protein kinase pathway by a novel mitogen-activated protein kinase phosphatase.
Dehydroepiandrosterone-sulfate, the sulfated form of dehydroepiandrosterone, is the most abundant steroid in young adults, but gradually declines with aging. In humans, the clinical application of dehydroepiandrosterone targeting some collagen diseases, such as systemic lupus erythematosus, as an adjunctive treatment has been applied in clinical trial. Here, we report that dehydroepiandrosterone may negatively regulate the mitogen-activated protein kinase pathway in humans via a novel dual specificity protein phosphatase, DDSP (dehydroepiandrosterone-enhanced dual specificity protein phosphatase). DDSP is highly homologous to LCPTP/HePTP, a tissue-specific protein tyrosine phosphatase (PTP) which negatively regulates both ERK and p38-mitogen-activated protein kinase, and is transcribed from the PTPN7 locus by alternative splicing. Although previous reports have shown that the mRNA expression of the LCPTP/HePTP gene was inducible by extracellular signals such as T-cell antigen receptor stimulation, reverse transcribed (RT)-PCR experiments using specific sets of primers suggested that the expression of LCPTP/HePTP was constitutive while the actual inducible sequence was that of DDSP. Furthermore DDSP was widely distributed among different types of human tissues and specifically interacted with p38-mitogen-activated protein kinase. This inducible negative regulation of the p38-mitogen-activated protein kinase-dependent pathway may help to clarify the broad range of dehydroepiandrosterone actions, thereby aiding the development of new preventive or adjunctive applications for human diseases.
Ashida
Kenji
K
Department of Medicine and Bioregulatory Science (3rd Department of Internal Medicine), Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
Goto
Kiminobu
K
Zhao
Yue
Y
Okabe
Taijiro
T
Yanase
Toshihiko
T
Takayanagi
Ryoichi
R
Nomura
Masatoshi
M
Nawata
Hajime
H
D000595:Amino Acid Sequence; D000818:Animals; D016367:Baculoviridae; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D003687:Dehydroepiandrosterone / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005822:Genetic Vectors; D005982:Glutathione Transferase; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D017931:DNA Primers; D018076:DNA, Complementary; D003687:Dehydroepiandrosterone; D005982:Glutathione Transferase; D048051:p38 Mitogen-Activated Protein Kinases; C500554:DDSP protein, human; D017027:Protein Tyrosine Phosphatases