Abstract
Smad family members are essential intracellular signaling components of the transforming growth factor-beta (TGF-β) superfamily involved in a range of biological activities. The loss of sensitivity to TGF-β is frequent in human lung cancers and inactivation of Smad family members are thought to play important roles in disruption of TGF-β signaling. In the study presented here, we characterized the biological and biochemical functions of six Smad2 and Smad4 mutants, which we previously identified in human lung cancers. All mutant Smad2 and Smad4 were in fact found to be defective in transmitting growth inhibitory signals originating from TGF-β and incapable of activating Smad/hFAST-1-mediated transcription. Transcriptional activation of plasminogen activator inhibitor type 1 (PAI-1) was impaired in four of the six mutants due to the defects in homo- and/or hetero-oligomerization with wild-type Smads. In contrast, the remaining two Smad mutants showed a modest reduction in the PAI-1 transcriptional activation and apparently retained the ability to oligomerize with wild-type Smads. Significant loss of growth inhibition and Smad/hFAST-1-mediated transcriptional activation by all of the six mutants suggested that Smad mutants are indeed functionally impaired Smad mutations and may play a role in lung tumorigenesis. Moreover, the present findings suggest that in addition to the impairment in the homo- and/or hetero-oligomerization, there may be an alternative mechanism producing disruption of TGF-β signaling, involving hFAST-1-or possibly other transcriptional cofactor(s)-mediated transcriptional activation.
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Acknowledgements
We would like to thank Dr T Hayakawa (Nagoya University School of Medicine) for his encouragement throughout this study, Dr C Harris (National Cancer Center Institute) for BEAS2B cells, Dr R Derynck (University of California) for p800-luc plasmid, Dr J Massagué (Memorial Sloan-Kettering Cancer Center) for wild-type TGF-βRI and TGF-βRI (TD) expression constructs and Dr B Vogelstein (Johns Hopkins Oncology Center) for hFAST-1 and FBE/SBE-lux constructs. This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture, Japan and a Grant-in-Aid for the Second Term Comprehensive Ten Year Strategy for Cancer Control from the Ministry of Health and Welfare, Japan.
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Yanagisawa, K., Uchida, K., Nagatake, M. et al. Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers. Oncogene 19, 2305–2311 (2000). https://doi.org/10.1038/sj.onc.1203591
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DOI: https://doi.org/10.1038/sj.onc.1203591
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