Expression of an oncogenic rasHa gene in murine keratinocytes induces tyrosine phosphorylation and reduced activity of protein kinase C delta.
Expression of an oncogenic rasHa gene in murine keratinocytes induces tyrosine phosphorylation and reduced activity of protein kinase C delta.
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鼠角质形成细胞中致癌 rasHa 基因的表达会诱导酪氨酸磷酸化并降低蛋白激酶 C δ 的活性。
DOI：
10.1016/s0021-9258(19)74282-3
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发表时间：
1993
期刊：
影响因子：
--
通讯作者：
S. H. Yuspa
中科院分区：
文献类型：
--
作者：
M. F. Denning;A. A. Dlugosz;M K Howett;S. H. Yuspa
表达致癌rasHa基因的小鼠角质形成细胞在体内产生良性肿瘤，并在体外对佛波醇酯的反应发生改变。用v-rasHa基因转导的培养的角质形成细胞（v-rasHa角质形成细胞）对Ca（2+）诱导的终末分化具有抗性，该终末分化是正常角质形成细胞中依赖于蛋白激酶C（PKC）活化的过程。角化细胞中表达的五种PKC亚型（α、δ、β、ζ和eta）在v-rasHa转化细胞中进行了定量或定性变化检查。未检测到定量变化，但PKC δ在v-rasHa角质形成细胞和表达c-rasHa基因激活等位基因的良性肿瘤角质形成细胞系中被酪氨酸磷酸化。对来自角质形成细胞的PKC δ的磷酸化和非磷酸化形式的分析表明，磷酸化的PKC δ不受佛波酯处理的刺激。蛋白激酶抑制剂staurosporine能够诱导v-rasHa角质形成细胞和良性肿瘤细胞系的分化，并且伴随着PKC δ的酪氨酸磷酸化降低。在表达致癌rasHa基因的细胞中酪氨酸激酶和PKC δ之间的这种相互作用可能代表肿瘤性角质形成细胞分化的分子阻滞。
Murine keratinocytes expressing an oncogenic rasHa gene produce benign tumors in vivo and demonstrate altered responses to phorbol esters in vitro. Cultured keratinocytes transduced with the v-rasHa gene (v-rasHa keratinocytes) are resistant to Ca(2+)-induced terminal differentiation, a process that is dependent on protein kinase C (PKC) activation in normal keratinocytes. Five PKC isoforms expressed in keratinocytes (alpha, delta, epsilon, zeta, and eta) were examined for quantitative or qualitative changes in v-rasHa-transformed cells. No quantitative changes were detected, but PKC delta was tyrosine-phosphorylated in v-rasHa keratinocytes and in benign neoplastic keratinocyte cell lines expressing an activated allele of the c-rasHa gene. Analysis of phosphorylated and non-phosphorylated forms of PKC delta from keratinocytes indicated that phosphorylated PKC delta was not stimulated by phorbol ester treatment. The protein kinase inhibitor staurosporine was able to induce differentiation in v-rasHa keratinocytes and benign tumor cell lines, and concomitantly tyrosine phosphorylation of PKC delta decreased. This interaction between tyrosine kinases and PKC delta in cells expressing an oncogenic rasHa gene may represent a molecular block to differentiation in neoplastic keratinocytes.