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ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-β/Smad-induced growth arrest of prostate cells

Oncogene volume 25, pages 5591–5600 (2006)Cite this article

Abstract

Transforming growth factor-β (TGF-β) elicits a potent growth inhibitory effect on many normal cells by binding to specific serine/threonine kinase receptors and activating specific Smad proteins, which regulate the expression of cell cycle genes, including the p21 cyclin-dependent kinase (CDK) inhibitor gene. Interestingly, cancer cells are often insensitive to the anti-mitogenic effects of TGF-β for which the molecular mechanisms are not well understood. In this study, we found that the candidate prostate cancer susceptibility gene ELAC2 potentiates TGF-β/Smad-induced transcriptional responses. ELAC2 associates with activated Smad2; the C-terminal MH2 domain of Smad2 interacts with the N-terminal region of ELAC2. Small interfering siRNA-mediated knock-down of ELAC2 in prostate cells suppressed TGF-β-induced growth arrest. Moreover, ELAC2 was shown to specifically associate with the nuclear Smad2 partner, FAST-1 and to potentiate the interaction of activated Smad2 with transcription factor Sp1. Furthermore, activation of the p21 CDK inhibitor promoter by TGF-β is potentiated by ELAC2. Taken together our data indicate an important transcriptional scaffold function for ELAC2 in TGF-β/Smad signaling mediated growth arrest.

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Acknowledgements

This research was supported by AstraZeneca Research Grant 2004 (SI), Kowa Life Science Foundation (SI), Kato Memorial Bioscience Foundation (SI), Japan Society for the Promotion Science (FI) and Grants-in-aid for Scientific Research and a grant of the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology (SI and MK) and Dutch Cancer Society and EC 6th framework STREP Tumor-Host Genomics (Pt-D). We thank Drs SV Tavtigian, B Vogelstein, A Moustakas, T Imamura and K Iwata for valuable reagents and Dr TR Brummelkamp for technical advices.

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  1. D Noda and S Itoh: These two authors equally contributed to this work.

Authors and Affiliations

  1. Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan

    D Noda, S Itoh, Y Watanabe, M Inamitsu, F Itoh & M Kato

  2. The Department of Otolaryngology, Yamagata University School of Medicine, Yamagata, Yamagata, Japan

    D Noda & S Koike

  3. Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    S Itoh, S Dennler, F Itoh & P ten Dijke

  4. Division of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Wolstein Research Building, Cleveland, OH, USA

    D Danielpour

  5. Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

    P ten Dijke

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Correspondence to S Itoh.

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Noda, D., Itoh, S., Watanabe, Y. et al. ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-β/Smad-induced growth arrest of prostate cells. Oncogene 25, 5591–5600 (2006). https://doi.org/10.1038/sj.onc.1209571

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