GADD45beta enhances Col10a1 transcription via the MTK1/MKK3/6/p38 axis and activation of C/EBPbeta-TAD4 in terminally differentiating chondrocytes.
Enviado por Miguel Otero el
Título | GADD45beta enhances Col10a1 transcription via the MTK1/MKK3/6/p38 axis and activation of C/EBPbeta-TAD4 in terminally differentiating chondrocytes. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Autores | Tsuchimochi, K, Otero, M, Dragomir, CL, Plumb, DA, Zerbini, LF, Libermann, TA, Marcu, KB, Komiya, S, Ijiri, K, Goldring, MB |
Journal | J Biol Chem |
Volume | 285 |
Issue | 11 |
Pagination | 8395-407 |
Date Published | 2010 Mar 12 |
ISSN | 1083-351X |
Palabras clave | Activating Transcription Factor 1, Animals, Antigens, Differentiation, CCAAT-Enhancer-Binding Protein-beta, Cell Differentiation, Cell Line, Tumor, Chondrocytes, Collagen Type X, Cyclic AMP Response Element-Binding Protein, Gene Expression Regulation, Developmental, Growth Plate, Humans, MAP Kinase Kinase 3, MAP Kinase Kinase 6, MAP Kinase Kinase Kinase 1, MAP Kinase Kinase Kinase 4, MAP Kinase Signaling System, Matrix Metalloproteinase 13, Mice, Mice, Inbred C57BL, p38 Mitogen-Activated Protein Kinases, Promoter Regions, Genetic, Teratocarcinoma, Transcription Factor AP-1, Transcription, Genetic |
Abstract | GADD45beta (growth arrest- and DNA damage-inducible) interacts with upstream regulators of the JNK and p38 stress response kinases. Previously, we reported that the hypertrophic zone of the Gadd45beta(-/-) mouse embryonic growth plate is compressed, and expression of type X collagen (Col10a1) and matrix metalloproteinase 13 (Mmp13) genes is decreased. Herein, we report that GADD45beta enhances activity of the proximal Col10a1 promoter, which contains evolutionarily conserved AP-1, cAMP-response element, and C/EBP half-sites, in synergism with C/EBP family members, whereas the MMP13 promoter responds to GADD45beta together with AP-1, ATF, or C/EBP family members. C/EBPbeta expression also predominantly co-localizes with GADD45beta in the embryonic growth plate. Moreover, GADD45beta enhances C/EBPbeta activation via MTK1, MKK3, and MKK6, and dominant-negative p38alphaapf, but not JNKapf, disrupts the combined trans-activating effect of GADD45beta and C/EBPbeta on the Col10a1 promoter. Importantly, GADD45beta knockdown prevents p38 phosphorylation while decreasing Col10a1 mRNA levels but does not affect C/EBPbeta binding to the Col10a1 promoter in vivo, indicating that GADD45beta influences the transactivation function of DNA-bound C/EBPbeta. In support of this conclusion, we show that the evolutionarily conserved TAD4 domain of C/EBPbeta is the target of the GADD45beta-dependent signaling. Collectively, we have uncovered a novel molecular mechanism linking GADD45beta via the MTK1/MKK3/6/p38 axis to C/EBPbeta-TAD4 activation of Col10a1 transcription in terminally differentiating chondrocytes. |
DOI | 10.1074/jbc.M109.038638 |
Alternate Journal | J. Biol. Chem. |
PubMed ID | 20048163 |
PubMed Central ID | PMC2832989 |
Grant List | AG022021 / AG / NIA NIH HHS / United States CA85467 / CA / NCI NIH HHS / United States GM066882 / GM / NIGMS NIH HHS / United States PC051217 / PC / NCI NIH HHS / United States R01 AG022021 / AG / NIA NIH HHS / United States R01 AG022021-08 / AG / NIA NIH HHS / United States RC4 AR060546 / AR / NIAMS NIH HHS / United States RC4 AR060546-01 / AR / NIAMS NIH HHS / United States |