The Role of c-Jun N-terminal Kinase (JNK) in Apoptosis Induced by Ultraviolet C and γ Radiation

doi:10.1074/jbc.271.50.31929

The Role of c-Jun N-terminal Kinase (JNK) in Apoptosis Induced by Ultraviolet C and γ Radiation

DURATION OF JNK ACTIVATION MAY DETERMINE CELL DEATH AND PROLIFERATION*

From the ^¶ Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030,
^∥ Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, and
^″ Howard Hughes Medical Institute and Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

^‴ A Scholar of the Leukemia Society of America. To whom correspondence should be addressed:
Dept. of Microbiology and Immunology, Baylor College of Medicine, M929, One Baylor Plaza, Houston, TX 77030.
Tel.: 713-798-4665; Fax: 713-798-3700; E-mail: ttan{at}bcm.tmc.edu

Abstract

c-Jun N-terminal kinases (JNKs) participate in cellular responses to mitogenic stimuli, environmental stresses, and apoptotic agents. The mechanisms by which JNK integrates with other signaling pathways and regulates the diverse cellular events are unclear. We found JNK, but not p38-mitogen-activated protein kinase (MAPK) or extracellular signal-regulated kinase 2, to be persistently activated in apoptosis induced by γ radiation, UV-C, and anti-Fas treatment. Direct correlation was found between JNK activation and apoptosis induced by UV-C and γ radiation; however, JNK induction and apoptosis induced by Fas signaling were not well correlated. Overexpression of activated JNK1 caused cell death in transfected cells, and the expression of a dominant-negative mutant of MAPK kinase 1 or JNK1 (but not a dominant-negative mutant of p38-MAPK or c-Raf) prevented the UV-C- and γ radiation-induced cell death. The inductions of JNK in T-cell activation and apoptosis were distinguished by the different activation patterns, transient versus persistent, respectively. Co-treatment with a tyrosine phosphatase inhibitor (sodium orthovanadate) and T-cell activation signals (phorbol 12-myristate 13-acetate plus ionomycin) prolonged JNK induction, followed by T-cell apoptosis. Our data revealed the requirement of the JNK pathway in radiation-induced apoptosis and implicated the importance of the duration of JNK activation in determining the cell fates.

Footnotes

↵* This work was supported by National Institutes of Health Grants R01-GM49875 and R01-AI38649 (to T.-H. T.).
↵¹ The abbreviations used are:

TNF

tumor necrosis factor

JNK

c-Jun N-terminal kinase

MAPK

mitogen-activated protein kinase

ERK

extracellular signal-regulated kinase

MEKK

mitogen-activated protein kinase kinase kinase

GST

glutathione S-transferase

PMA

phorbol 12-myristate 13-acetate

ICE

interleukin-1β-converting enzyme

Ab

antibody

CMV

cytomegalovirus

PBS

phosphate-buffered saline

X-gal

5-bromo-4-chloro-3-indoyl β-D-galactoside

MOPS

4-morpholinepropanesulfonic acid

NGF

nerve growth factor.
- Received March 1, 1996.
- Revision received July 25, 1996.