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Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene

Oncogene volume 24, pages 5878–5887 (2005)Cite this article

Abstract

Gain-of-function mutation of the K-ras gene is one of the most common genetic changes in human tumors. In tumors carrying K-ras mutation, the presence of oncogenic K-Ras is necessary for maintenance of the transformed phenotype. ESXR1 is a human paired-like homeodomain-containing protein expressed primarily in the testis. In cells, the 65-kDa full-length ESXR1 protein is proteolytically processed into an N-terminal 45-kDa fragment containing the homeodomain, which localizes exclusively within the nucleus, and a C-terminal 20-kDa fragment consisting of a proline-rich repeat region, which is located in the cytoplasm. In this work, we demonstrated that the N-terminal ESXR1 fragment specifically recognizes the TAATNNNATTA P3 consensus sequence for the paired-like homeodomain and functions as a sequence-specific transcriptional repressor. We also showed that the N-terminal ESXR1 fragment binds to the TAATGTTATTA sequence present within the first intron of the human K-ras gene and inhibits its expression at both mRNA and protein levels. Ectopic expression of the N-terminal ESXR1 fragment in human carcinoma cells that carry mutated K-ras reduces the level of K-Ras and thereby inhibits the tumor cell proliferation. Identification of ESXR1 as a transcriptional repressor of K-ras has an important implication for the development of cancer therapy that inhibits oncogenic K-Ras expression.

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Acknowledgements

We thank A Kakita, S Ashizawa, H Higashi, H Ozawa, K Yokoyama, T Ueno, J Hamada, S Takiya and H Meguro for technical assistance. This work was supported by grants-in-aid for science research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.

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Authors and Affiliations

  1. Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, 060-0815, Sapporo, Japan

    Masatomo Yanagihara, Susumu Ishikawa, Masanori Naito, Junta Nakajima & Masanori Hatakeyama

  2. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan

    Hiroyuki Aburatani

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  1. Masatomo Yanagihara
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  2. Susumu Ishikawa
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Correspondence to Masanori Hatakeyama.

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Yanagihara, M., Ishikawa, S., Naito, M. et al. Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene. Oncogene 24, 5878–5887 (2005). https://doi.org/10.1038/sj.onc.1208736

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