Carrier F, Zhan Q, Alamo I, Hanaoka F, Fornace A J
Laboratory of Molecular Pharmacology, DTP, DCT, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Biochem Pharmacol. 1998 Mar 15;55(6):853-61. doi: 10.1016/s0006-2952(97)00592-3.
We have evaluated the role of various protein kinases on the induction of the gadd (growth arrest and DNA damage inducible) genes, using a panel of protein kinase inhibitors. Our data indicate that three different stress response pathways mediating gadd gene induction are most likely regulated by different protein kinases or combinations of protein kinases. The protein kinase inhibitor staurosporine and the temperature sensitive (ts) p34cdc2 mutant reduced induction by the alkylating agent methylmethane sulfonate (MMS) of the rodent gadd45 and gadd153 genes. However, staurosporine had no effect of the ionizing radiation (IR) induction of the human GADD45. Caffeine and 2-aminopurine, on the other hand, completely blocked this IR induction. Suramin, an antitumor drug that interferes with the interaction of growth factors with their receptors, inhibited the UV radiation induction of GADD45 and GADD153 but had no effect on the MMS and IR pathways. Elevated expression of gadd45 by medium depletion (starvation) was partially reduced by the addition of either genistein or tyrphostin, two protein tyrosine kinase inhibitors, while gadd153 was affected by tyrphostin only. Two inhibitors acting preferentially on cAMP-dependent protein kinase (PKA), N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide, HCl (H8) and protein kinase inhibitor (PKI), also had a moderate effect on the medium depletion-induced levels of both gadd genes. Thus, these varied effects of inhibitors on gadd gene responses point to important differences in the pathways controlling these responses.
我们使用一组蛋白激酶抑制剂评估了各种蛋白激酶在诱导gadd（生长停滞和DNA损伤诱导）基因方面的作用。我们的数据表明，介导gadd基因诱导的三种不同应激反应途径很可能受不同蛋白激酶或蛋白激酶组合的调控。蛋白激酶抑制剂星形孢菌素和温度敏感型（ts）p34cdc2突变体降低了啮齿动物gadd45和gadd153基因被烷基化剂甲磺酸甲酯（MMS）诱导的水平。然而，星形孢菌素对人GADD45的电离辐射（IR）诱导没有影响。另一方面，咖啡因和2-氨基嘌呤完全阻断了这种IR诱导。苏拉明是一种干扰生长因子与其受体相互作用的抗肿瘤药物，它抑制了GADD45和GADD153的紫外线辐射诱导，但对MMS和IR途径没有影响。通过培养基耗尽（饥饿）使gadd45表达升高，添加两种蛋白酪氨酸激酶抑制剂染料木黄酮或 tyrphostin后部分降低，而gadd153仅受tyrphostin影响。两种优先作用于cAMP依赖性蛋白激酶（PKA）的抑制剂，N-[2-（甲氨基）乙基]-5-异喹啉磺酰胺盐酸盐（H8）和蛋白激酶抑制剂（PKI），对培养基耗尽诱导的两种gadd基因水平也有适度影响。因此，抑制剂对gadd基因反应的这些不同影响表明控制这些反应的途径存在重要差异。
