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RhoB, not RhoA, represses the transcription of the transforming growth factor beta type II receptor by a mechanism involving activator protein 1.
J Biol Chem. 2002 Mar 08; 277(10):8500-7.JB

Abstract

The transforming growth factor-beta (TGF-beta) type I (T beta R-I) and type II (T beta R-II) receptors are responsible for transducing TGF-beta signals. We have previously shown that inhibition of farnesyltransferase activity results in an increase in T beta R-II expression, leading to enhanced TGF-beta binding, signaling, and inhibition of tumor cell growth, suggesting that a farnesylated protein(s) exerts a repressive effect on T beta R-II expression. Likely candidates are farnesylated proteins such as Ras and RhoB, which are both farnesylated and involved in cell growth control. Neither a dominant negative Ha-Ras, constitutively activated Ha-Ras, or a pharmacological inhibitor of MEK1 affected T beta R-II transcription. However, ectopic expression of RhoB, but not the closely related family member RhoA, resulted in a 5-fold decrease of T beta R-II promoter activity. Furthermore, ectopic expression of RhoB, but not RhoA, resulted in a significant decrease of T beta R-II protein expression and resistance of tumor cells to TGF-beta-mediated cell growth inhibition. Deletion analysis of the T beta R-II promoter identified a RhoB-responsive region, and mutational analysis of this region revealed that a site for the transcription factor activator protein 1 (AP1) is critical for RhoB-mediated repression of T beta R-II transcription. Electrophoretic mobility shift assays clearly showed that the binding of AP1 to its DNA-binding site is strongly inhibited by RhoB. Consequently, transcription assays using an AP1 reporter showed that AP1-mediated transcription is down-regulated by RhoB. Altogether, these results identify a mechanism by which RhoB antagonizes TGF-beta action through transcriptional down-regulation of AP1 in T beta R-II promoter.

Authors+Show Affiliations

Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Oncology, University of South Florida, Tampa, Florida 33612, USA.No 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

11741970

Citation

Adnane, Jalila, et al. "RhoB, Not RhoA, Represses the Transcription of the Transforming Growth Factor Beta Type II Receptor By a Mechanism Involving Activator Protein 1." The Journal of Biological Chemistry, vol. 277, no. 10, 2002, pp. 8500-7.
Adnane J, Seijo E, Chen Z, et al. RhoB, not RhoA, represses the transcription of the transforming growth factor beta type II receptor by a mechanism involving activator protein 1. J Biol Chem. 2002;277(10):8500-7.
Adnane, J., Seijo, E., Chen, Z., Bizouarn, F., Leal, M., Sebti, S. M., & Muñoz-Antonia, T. (2002). RhoB, not RhoA, represses the transcription of the transforming growth factor beta type II receptor by a mechanism involving activator protein 1. The Journal of Biological Chemistry, 277(10), 8500-7.
Adnane J, et al. RhoB, Not RhoA, Represses the Transcription of the Transforming Growth Factor Beta Type II Receptor By a Mechanism Involving Activator Protein 1. J Biol Chem. 2002 Mar 8;277(10):8500-7. PubMed PMID: 11741970.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RhoB, not RhoA, represses the transcription of the transforming growth factor beta type II receptor by a mechanism involving activator protein 1. AU - Adnane,Jalila, AU - Seijo,Edward, AU - Chen,Zhi, AU - Bizouarn,Francisco, AU - Leal,Martha, AU - Sebti,Said M, AU - Muñoz-Antonia,Teresita, Y1 - 2001/12/11/ PY - 2001/12/14/pubmed PY - 2002/4/16/medline PY - 2001/12/14/entrez SP - 8500 EP - 7 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 277 IS - 10 N2 - The transforming growth factor-beta (TGF-beta) type I (T beta R-I) and type II (T beta R-II) receptors are responsible for transducing TGF-beta signals. We have previously shown that inhibition of farnesyltransferase activity results in an increase in T beta R-II expression, leading to enhanced TGF-beta binding, signaling, and inhibition of tumor cell growth, suggesting that a farnesylated protein(s) exerts a repressive effect on T beta R-II expression. Likely candidates are farnesylated proteins such as Ras and RhoB, which are both farnesylated and involved in cell growth control. Neither a dominant negative Ha-Ras, constitutively activated Ha-Ras, or a pharmacological inhibitor of MEK1 affected T beta R-II transcription. However, ectopic expression of RhoB, but not the closely related family member RhoA, resulted in a 5-fold decrease of T beta R-II promoter activity. Furthermore, ectopic expression of RhoB, but not RhoA, resulted in a significant decrease of T beta R-II protein expression and resistance of tumor cells to TGF-beta-mediated cell growth inhibition. Deletion analysis of the T beta R-II promoter identified a RhoB-responsive region, and mutational analysis of this region revealed that a site for the transcription factor activator protein 1 (AP1) is critical for RhoB-mediated repression of T beta R-II transcription. Electrophoretic mobility shift assays clearly showed that the binding of AP1 to its DNA-binding site is strongly inhibited by RhoB. Consequently, transcription assays using an AP1 reporter showed that AP1-mediated transcription is down-regulated by RhoB. Altogether, these results identify a mechanism by which RhoB antagonizes TGF-beta action through transcriptional down-regulation of AP1 in T beta R-II promoter. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/11741970/RhoB_not_RhoA_represses_the_transcription_of_the_transforming_growth_factor_beta_type_II_receptor_by_a_mechanism_involving_activator_protein_1_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11741970 DB - PRIME DP - Unbound Medicine ER -