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ARK5 is transcriptionally regulated by the Large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma

Oncogene volume 24, pages 6936–6944 (2005)Cite this article

Abstract

ARK5, AMP-activated protein kinase (AMPK)-related protein kinase mediating Akt signals, is closely involved in tumor progression, and its stage-associated expression was observed in colorectal cancer. In this study, we found ARK5 expression in multiple myeloma cell lines expressing c-MAF and MAFB. In addition, gene expression profiling of 351 clinical specimens revealed ARK5 expression in primary myelomas expressing c-MAF and MAFB, suggesting that ARK5 may be a transcriptional target of the Large-MAF family. Sequence analysis of the ARK5 gene promoter revealed that it contains two putative MAF-recognition element (MARE) sequences. In support of this hypothesis, ARK5 was induced when an MAFB or c-MAF expression vector was introduced into non-ARK5-expressing colon cancer cells. Furthermore, ARK5 promoter activity was dramatically decreased by mutation or deletion of MARE sequences. Chromatin immunoprecipitation assays revealed an interaction between the Large-MAF family proteins and MARE sequences in the ARK5 promoter. Moreover, in ARK5 mRNA-expressing multiple myeloma lines, but not in ARK5-negative lines, insulin-like growth factor (IGF)-1 increased invasion activity. IGF-1-induced invasion was reproduced when ARK5 was overexpressed in Burkitt's lymphoma and plasmacytoma lines. Based on results, we conclude that ARK5 is a transcriptional target of the Large-MAF family through MARE sequence and that ARK5 may in part mediate the aggressive phenotype associated with c-MAF- and MAFB-expressing myelomas.

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Acknowledgements

This work was partly supported by Grants for the 2nd- and 3rd-Term Comprehensive 10-year Strategy of Cancer Control from the Ministry of Health, Welfare and Labour, Grant for the Medical Frontier Program from the Ministry of Health, Welfare and Labour, and Research Grant of the Princess Takamatsu Cancer Research Fund. AS is the recipient of a Research Resident Fellowship from the Foundation for Promotion of Cancer Research. This research was supported by The Fund to Cure Myeloma (JS) and by NIH Grants CA55819 (JS) and CA97513 (JS) from the National Cancer Institute, Bethesda, MD, USA.

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Author notes

  1. Atsushi Suzuki

    Present address: National Institute for Physiological Sciences, Aichi, 444-8585, Japan

Authors and Affiliations

  1. Cancer Physiology Project, National Cancer Center Research Institute East, 6-5-1 Kashiwanoha, Kashiwa, 277-8577, Chiba, Japan

    Atsushi Suzuki, Tsutomu Ogura & Hiroyasu Esumi

  2. Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-chou, 467-8601, Nagoya, Japan

    Shinsuke Iida, Miyuki Kato-Uranishi, Emi Tajima & Ryuzo Ueda

  3. Donna D and Donald M Lambert Laboratory of Myeloma Genetics at the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, 72205, AR, USA

    Fenghuang Zhan, Ichiro Hanamura, Yongsheng Huang, Bart Barlogie & John Shaughnessy Jr

  4. Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1, Tennodai, 305-8575, Tsukuba, Japan

    Satoru Takahashi

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Correspondence to Hiroyasu Esumi.

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Suzuki, A., Iida, S., Kato-Uranishi, M. et al. ARK5 is transcriptionally regulated by the Large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma. Oncogene 24, 6936–6944 (2005). https://doi.org/10.1038/sj.onc.1208844

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