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The c-Abl tyrosine kinase stabilizes Pitx1 in the apoptotic response to DNA damage

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Abstract

In the DNA damage response, c-Abl tyrosine kinase is transiently accumulated in the nucleus and induces apoptosis; however, little is known about the mechanism underlying apoptosis induction via nuclear c-Abl. Here we demonstrate that the expression of human pituitary homeobox 1 (Pitx1) transcription factor is increased after DNA damage. Notably, c-Abl controls augmentation of Pitx1 at the post-transcriptional level. Overexpression of c-Abl induces tyrosine phosphorylation of Pitx1, either directly or indirectly. We also show that, upon exposure to genotoxic stress, overexpression of Pitx1 is associated with marked induction of apoptosis that is independent of p53 status. Importantly, inhibition of c-Abl kinase activity substantially attenuates Pitx1-mediated apoptosis. These findings provide evidence that c-Abl participates in modulating Pitx1 expression in the apoptotic response to DNA damage.

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Acknowledgements

The authors thank Dr. Lobie for GFP-Pitx1 plasmid. This work was supported by grants from the Ministry of Education, Science and Culture of Japan (to K.Y. and Y.M.), Takeda Science Foundation (to K.Y.), Senri Life Science Foundation (to K.Y.), Kowa Life Science Foundation (to K.Y.), and Sankyo Foundation of Life Science (to K.Y.).

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Authors and Affiliations

  1. Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan

    Tomoko Yamaguchi, Yoshio Miki & Kiyotsugu Yoshida

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  1. Tomoko Yamaguchi
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  2. Yoshio Miki
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  3. Kiyotsugu Yoshida
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Correspondence to Kiyotsugu Yoshida.

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K. Yoshida and Y. Miki share senior authorship.

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Yamaguchi, T., Miki, Y. & Yoshida, K. The c-Abl tyrosine kinase stabilizes Pitx1 in the apoptotic response to DNA damage. Apoptosis 15, 927–935 (2010). https://doi.org/10.1007/s10495-010-0488-6

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  • DOI: https://doi.org/10.1007/s10495-010-0488-6

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