c-Jun N-terminal kinase is essential for growth of human T98G glioblastomacells

The c-Jun N-terminal kinase/stress-activated protein kinase (JNR/SAPK) path way is activated by numerous cellular stresses. Although it has been implic ated in me diating apoptosis and growth factor signaling, its role in regul ating cell growth is not yet clear. Here, the influence of JNK on basal (un stimulated) growth of human tumor glioblastoma T98G cells was investigated using highly specific JNK antisense oligonucleotides to inhibit JNK express ion. Transient depletion of either JNK1 or JNK2 suppressed cell growth asso ciated with an inhibition of DNA synthesis and cell cycle arrest in S phase . The growth-inhibitory potency of JNK2 antisense ((JNK)2 IC50 = 0.14 mu M) was greater than that of JNK1 antisense ((JNK)1 IC50 = 0.37 mu M), suggest ing that JNK2 plays a dominant role in regulating growth of T98G cells. Ind eed, JNK2 antisense-treated populations exhibited greater inhibition of DNA synthesis and accumulation of S-phase cells than did the JNK1 antisense-tr eated cultures, with a significant proportion of these cells detaching from the tissue culture plate. JNK2 (but not JNK1) antisense-treated cultures e xhibited marked elevation in the expression of the cyclin-dependent kinase inhibitor p21(cip1/waf1) accompanied by inhibition of Cdk2/Cdc2 kinase acti vities. Taken together, these results indicate that JNK is required for gro wth of T98G cells in nonstress conditions and that p21(cip1/waf1) may contr ibute to the sustained growth arrest of JNK2-depleted T98G cultures.