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TGF-beta1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70S6k.
Am J Physiol Gastrointest Liver Physiol. 2004 Nov; 287(5):G974-87.AJ

Abstract

Transforming growth factor-beta1 (TGF-beta1), the main cytokine involved in liver fibrogenesis, induces expression of the type I collagen genes in hepatic stellate cells by a transcriptional mechanism, which is hydrogen peroxide and de novo protein synthesis dependent. Our recent studies have revealed that expression of type I collagen and matrix metalloproteinase-13 (MMP-13) mRNAs in hepatic stellate cells is reciprocally modulated. Because TGF-beta1 induces a transient elevation of alpha1(I) collagen mRNA, we investigated whether this cytokine was able to induce the expression of MMP-13 mRNA during the downfall of the alpha1(I) collagen mRNA. In the present study, we report that TGF-beta1 induces a rapid decline in steady-state levels of MMP-13 mRNA at the time that it induces the expression of alpha1(I) collagen mRNA. This change in MMP-13 mRNA expression occurs within the first 6 h postcytokine administration and is accompanied by a twofold increase in gene transcription and a fivefold decrease in mRNA half-life. This is followed by increased expression of MMP-13 mRNA, which reaches maximal values by 48 h. Our results also show that this TGF-beta1-mediated effect is de novo protein synthesis-dependent and requires the activity of p38MAPK, phosphatidylinositol 3-kinase, AKT, and p70(S6k). Altogether, our data suggest that regulation of MMP-13 by TGF-beta1 is a complex process involving transcriptional and posttranscriptional mechanisms.

Authors+Show Affiliations

Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15246963

Citation

Lechuga, Carmen G., et al. "TGF-beta1 Modulates Matrix Metalloproteinase-13 Expression in Hepatic Stellate Cells By Complex Mechanisms Involving p38MAPK, PI3-kinase, AKT, and P70S6k." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 287, no. 5, 2004, pp. G974-87.
Lechuga CG, Hernández-Nazara ZH, Domínguez Rosales JA, et al. TGF-beta1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70S6k. Am J Physiol Gastrointest Liver Physiol. 2004;287(5):G974-87.
Lechuga, C. G., Hernández-Nazara, Z. H., Domínguez Rosales, J. A., Morris, E. R., Rincón, A. R., Rivas-Estilla, A. M., Esteban-Gamboa, A., & Rojkind, M. (2004). TGF-beta1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70S6k. American Journal of Physiology. Gastrointestinal and Liver Physiology, 287(5), G974-87.
Lechuga CG, et al. TGF-beta1 Modulates Matrix Metalloproteinase-13 Expression in Hepatic Stellate Cells By Complex Mechanisms Involving p38MAPK, PI3-kinase, AKT, and P70S6k. Am J Physiol Gastrointest Liver Physiol. 2004;287(5):G974-87. PubMed PMID: 15246963.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TGF-beta1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70S6k. AU - Lechuga,Carmen G, AU - Hernández-Nazara,Zamira H, AU - Domínguez Rosales,José-Alfredo, AU - Morris,Elena R, AU - Rincón,Ana Rosa, AU - Rivas-Estilla,Ana María, AU - Esteban-Gamboa,Andrés, AU - Rojkind,Marcos, Y1 - 2004/07/08/ PY - 2004/7/13/pubmed PY - 2004/12/16/medline PY - 2004/7/13/entrez SP - G974 EP - 87 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am J Physiol Gastrointest Liver Physiol VL - 287 IS - 5 N2 - Transforming growth factor-beta1 (TGF-beta1), the main cytokine involved in liver fibrogenesis, induces expression of the type I collagen genes in hepatic stellate cells by a transcriptional mechanism, which is hydrogen peroxide and de novo protein synthesis dependent. Our recent studies have revealed that expression of type I collagen and matrix metalloproteinase-13 (MMP-13) mRNAs in hepatic stellate cells is reciprocally modulated. Because TGF-beta1 induces a transient elevation of alpha1(I) collagen mRNA, we investigated whether this cytokine was able to induce the expression of MMP-13 mRNA during the downfall of the alpha1(I) collagen mRNA. In the present study, we report that TGF-beta1 induces a rapid decline in steady-state levels of MMP-13 mRNA at the time that it induces the expression of alpha1(I) collagen mRNA. This change in MMP-13 mRNA expression occurs within the first 6 h postcytokine administration and is accompanied by a twofold increase in gene transcription and a fivefold decrease in mRNA half-life. This is followed by increased expression of MMP-13 mRNA, which reaches maximal values by 48 h. Our results also show that this TGF-beta1-mediated effect is de novo protein synthesis-dependent and requires the activity of p38MAPK, phosphatidylinositol 3-kinase, AKT, and p70(S6k). Altogether, our data suggest that regulation of MMP-13 by TGF-beta1 is a complex process involving transcriptional and posttranscriptional mechanisms. SN - 0193-1857 UR - https://www.unboundmedicine.com/medline/citation/15246963/TGF_beta1_modulates_matrix_metalloproteinase_13_expression_in_hepatic_stellate_cells_by_complex_mechanisms_involving_p38MAPK_PI3_kinase_AKT_and_p70S6k_ L2 - https://journals.physiology.org/doi/10.1152/ajpgi.00264.2003?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -