MEMBRANE SIGNAL TRANSDUCTION IN TUMOR PROMOTION

这些研究的目的是确定所需的生化 肿瘤启动子-受体相互作用 以及肿瘤转化效应子的激活。 候选的第二信使包括蛋白质磷酸化， 活性氧生成和钙动员。 两 蛋白激酶C（PKC）的激活和随后的蛋白激酶C的丢失。 PKC活性可能在12-0- TPA促进的 转型 已发现80 kDa的C-激酶底物 在P-、P+和肿瘤中差异磷酸化 转化的JB 6细胞，具有很少或没有磷酸化的80-kDa 在转化细胞中观察到的磷蛋白（pp 80）。 pp 80是 被认为是肿瘤抑制因子。 的药理学类似物 钙，镧系元素，促进肿瘤转化， JB 6细胞通过PKC非依赖性途径。 镧系元素 佛波醇酯，诱导转化（活化）pro-1-或pro- 2-转染的P-细胞。 这表明肿瘤促进剂可以 与激活的原基因合作， PKC依赖性或PKC非依赖性转化 途径。 15和16 kDa的核蛋白的合成是 TPA在P+细胞中可诱导，但在P-细胞中不可诱导，这一事件可能 部分原因是P+细胞的促进敏感性。 最后，P+和P-细胞在短暂的TPA刺激的 与病灶相关的细胞P21 H-ras表达和 肌动蛋白构型的不可逆变化，表明可能的 细胞骨架、细胞质和核蛋白的协同作用 与激活的原基因结合来转化。

The goal of these studies is to determine the required biochemical events that occur between tumor promoter-receptor interaction and the activation of effectors of neoplastic transformation. Candidate second messengers include protein phosphorylation, reactive oxygen generation, and calcium mobilization. Both activation of protein kinase C (PKC) and the subsequent loss of PKC activity may be on the signal transduction pathway for 12-0- tretradecanoylphorbol-13-acetate (TPA)-promoted transformation. A C-kinase substrate of 80 kDa has been found to be differentially phosphorylated in P-, P+, and neoplastically transformed JB6 cells, with little or no phosphorylated 80-kDa phosphoprotein (pp80) seen in transformed cells. This pp80 is postulated to be a tumor suppressor. Pharmacological analogs of calcium, the lanthanides, promote neoplastic transformation in JB6 cells by a PKC-independent pathway. The lanthanides, like phorbol esters, induce transformation in (activated) pro-1- or pro- 2-transfected P- cells. This indicates that tumor promoters can collaborate with activated pro genes to bring about neoplastic transformation by either PKC-dependent or PKC-independent pathways. The synthesis of nuclear proteins of 15 and 16 kDa is TPA inducible in P+, but no in P- cells, an event that may account, in part, for the promotion sensitivity of P+ cells. Finally, P+ and P- cells differ in a transient, TPA-stimulated focus-associated expression of cellular P21 H-ras and an irreversible change in actin configuration, suggesting a possible collaboration of cytoskeletal, cytoplasmic and nuclear proteins with activated pro genes to bring about transformation.