Mammalian nitrilase 1 homologue Nit1 is a negative regulator in T cells.
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.
Zhang
Haibing
H
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Hou
Ying-Ju
YJ
Han
Shuang-Yin
SY
Zhang
Eric C
EC
Huebner
Kay
K
Zhang
Jianke
J
D000619:Aminohydrolases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D004249:DNA Damage / Q000276:immunology; D025461:Feedback, Physiological; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
D018797:Cell Cycle Proteins; D019014:fas Receptor; D000619:Aminohydrolases; C021867:nitrilase; D002118:Calcium