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International Immunology Advance Access originally published online on April 24, 2009
International Immunology 2009 21(6):691-703; doi:10.1093/intimm/dxp038
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© The Japanese Society for Immunology. 2009. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Mammalian nitrilase 1 homologue Nit1 is a negative regulator in T cells

Haibing Zhang1,*, Ying-Ju Hou1,*, Shuang-Yin Han1,3, Eric C. Zhang1, Kay Huebner2 and Jianke Zhang1

1 Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
2 Comprehensive Cancer Center and Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA
3 Present address: Center for Research, Henan Provincial People's Hospital, Zhengzhou 450003, China

Correspondence to: J. Zhang; E-mail: jzhang{at}mail.jci.tju.edu

The mammalian Nit1 protein is homologous to plant and bacterial nitrilases. In flies and worms, Nit1 is fused to the 5' end of Fhit, suggesting that Nit1 may functionally interact with the Fhit pathway. Fhit has been shown to play a role of a tumor suppressor. Somatic loss of Fhit in human tissues is associated with a wide variety of cancers. Deletion of Fhit results in a predisposition to induced and spontaneous tumors in mice. It has been suggested that Nit1 collaborates with Fhit in tumor suppression. Similar to mice lacking Fhit, Nit1-deficient mice are more sensitive to carcinogen-induced tumors. It was previously shown that ectopic expression of Nit1 or Fhit led to caspase activation and apoptosis, and that both proteins may play a role in DNA damage-induced apoptosis. In this study, we analyzed the physiological function of Nit1 in T cells using Nit1-knockout mice. Nit1-deficient T cells can undergo apoptosis induced by DNA damage due to irradiation and chemical treatment. However, apoptosis induced by Fas or Ca++ signals appeared to be compromised. Additionally, Nit1 deficiency resulted in T cell hyperproliferative responses induced by TCR stimulation. The expressions of T cell activation markers were elevated in Nit1–/– T cells. There was a spontaneous cell cycle entry and enhanced cell cycle progression in Nit1–/– T cells. These data indicate that Nit1 is a novel negative regulator in primary T cells.

Keywords: apoptosis, cell cycle, proliferation, T cells, tumor suppressor

* These are equal first authors.

Transmitting editor: S. Nagata

Received 22 October 2008, accepted 30 March 2009.


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