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Molecular and Cellular Biology, March 2000, p. 1713-1722, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Inhibition of c-Jun N-Terminal Kinase 2 Expression
Suppresses Growth and Induces Apoptosis of Human Tumor Cells in a
p53-Dependent Manner
Olga
Potapova,1
Myriam
Gorospe,1
Ryan H.
Dougherty,1
Nicholas M.
Dean,2
William A.
Gaarde,2 and
Nikki J.
Holbrook1,*
Cell Stress and Aging Section, Laboratory of
Biological Chemistry, National Institute on Aging, National Institutes
of Health, Baltimore, Maryland 21224,1 and
Isis Pharmaceuticals, Inc., Carlsbad, California
920082
Received 7 July 1999/Returned for modification 11 August
1999/Accepted 10 November 1999
c-Jun N-terminal kinase (JNK) plays a critical role in coordinating
the cellular response to stress and has been implicated in regulating
cell growth and transformation. To investigate the growth-regulatory
functions of JNK1 and JNK2, we used specific antisense oligonucleotides
(AS) to inhibit their expression. A survey of several human tumor cell
lines revealed that JNKAS treatment markedly inhibited the growth of
cells with mutant p53 status but not that of cells with normal p53
function. To further examine the influence of p53 on cell sensitivity
to JNKAS treatment, we compared the responsiveness of RKO, MCF-7, and
HCT116 cells with normal p53 function to that of RKO E6, MCF-7 E6, and
HCT116 p53
/
, which were rendered p53 deficient by
different methods. Inhibition of JNK2 (and to a lesser extent JNK1)
expression dramatically reduced the growth of p53-deficient cells but
not that of their normal counterparts. JNK2AS-induced growth inhibition
was correlated with significant apoptosis. JNK2AS treatment induced the
expression of the cyclin-dependent kinase inhibitor
p21Cip1/Waf1 in parental MCF-7, RKO, and HCT116
cells but not in the p53-deficient derivatives. That
p21Cip1/Waf1 expression contributes to the
survival of JNK2AS-treated cells was supported by additional
experiments demonstrating that p21Cip1/Waf1
deficiency in HCT116 cells also results in heightened sensitivity to
JNKAS treatment. Our results indicate that perturbation of JNK2
expression adversely affects the growth of otherwise nonstressed cells.
p53 and its downstream effector p21Cip1/Waf1
are important in counteracting these detrimental effects and promoting
cell survival.
*
Corresponding author. Mailing address: Laboratory of
Biological Chemistry, GRC, NIA, 5600 Nathan Shock Dr., Box 12, Baltimore, MD 21224. Phone: (410) 558-8446. Fax: (410) 558-8386. E-mail: nikki_holbrook{at}nih.gov.
Molecular and Cellular Biology, March 2000, p. 1713-1722, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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