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Molecular and Cellular Biology, April 2006, p. 2758-2771, Vol. 26, No. 7
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.7.2758-2771.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Overlapping Roles for Homeodomain-Interacting Protein Kinases Hipk1 and Hipk2 in the Mediation of Cell Growth in Response to Morphogenetic and Genotoxic Signals{dagger}

Kyoichi Isono,1 Kazumi Nemoto,1 Yuanyuan Li,2 Yuki Takada,1 Rie Suzuki,1 Motoya Katsuki,3 Akira Nakagawara,2 and Haruhiko Koseki1*

RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan,1 Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan,2 National Institute for Basic Biology, Okazaki National Research Institute, Okazaki, Japan3

Received 5 September 2005/ Returned for modification 3 October 2005/ Accepted 3 January 2006

Homeodomain-interacting protein kinase 1 (Hipk1), 2, and 3 genes encode evolutionarily conserved nuclear serine/threonine kinases, which were originally identified as interacting with homeodomain-containing proteins. Hipks have been repeatedly identified as interactors for a vast range of functional proteins, including not only transcriptional regulators and chromatin modifiers but also cytoplasmic signal transducers, transmembrane proteins, and the E2 component of SUMO ligase. Gain-of-function experiments using cultured cells indicate growth regulatory roles for Hipks on receipt of morphogenetic and genotoxic signals. However, Hipk1 and Hipk2 singly deficient mice were grossly normal, and this is expected to be due to a functional redundancy between Hipk1 and Hipk2. Therefore, we addressed the physiological roles of Hipk family proteins by using Hipk1 Hipk2 double mutants. Hipk1 Hipk2 double homozygotes are progressively lost between 9.5 and 12.5 days postcoitus and frequently fail to close the anterior neuropore and exhibit exencephaly. This is most likely due to defective proliferation in the neural fold and underlying paraxial mesoderm, particularly in the ventral region, which may be attributed to decreased responsiveness to Sonic hedgehog signals. The present study indicated the overlapping roles for Hipk1 and Hipk2 in mediating cell proliferation and apoptosis in response to morphogenetic and genotoxic signals during mouse development.

* Corresponding author. Mailing address: RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan. Phone: 81-45-503-9689. Fax: 81-45-503-9688. E-mail: koseki{at}rcai.riken.jp.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2006, p. 2758-2771, Vol. 26, No. 7
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.7.2758-2771.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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