noxin, a Novel Stress-Induced Gene Involved in Cell Cycle and Apoptosis

Abstract

We describe a novel stress-induced gene, noxin, and a knockout mouse line with an inactivated noxin gene. The noxin gene does not have sequelogs in the genome and encodes a highly serine-rich protein with predicted phosphorylation sites for ATM, Akt, and DNA-dependent protein kinase kinases; nuclear localization signals; and a Zn finger domain. noxin mRNA and protein levels are under tight control by the cell cycle. noxin, identified as a nitric oxide-inducible gene, is strongly induced by a wide range of stress signals: γ- and UV irradiation, hydrogen peroxide, adriamycin, and cytokines. This induction is dependent on p53. Noxin accumulates in the nucleus in response to stress and, when ectopically expressed, Noxin arrests the cell cycle at G₁; although it also induces p53, the cell cycle arrest function of Noxin is independent of p53 activity. noxin knockout mice are viable and fertile; however, they have an enlarged heart, several altered hematopoietic parameters, and a decreased number of spermatids. Importantly, loss or downregulation of Noxin leads to increased cell death. Our results suggest that Noxin may be a component of the cell defense system: it is activated by various stress stimuli, helps cells to withdraw from cycling, and opposes apoptosis.

We thank Masashi Narita, Vivek Mittal, Ravi Kandasamy, Stephen Hearn, Prasanth Kannanganattu, David Spector, Yuri Lazebnik, and Scott Lowe for advice and reagents. We thank Barbara Mish, Kimberly Lavine, Mirjam Hildebrand, and Pam Moody for excellent assistance. We also thank Julian Banerji for stimulating discussions and critical reading of the manuscript.

D.H. was a member of the CSHL Undergraduate Research Program. Support to G.E. was provided by NINDS, the Ira Hazan Fund, the Charles Leach II Foundation, the Eppley Foundation for Research, and The Seraph Foundation.