The inducible expression of dominant-negative epidermal growth factor receptor-CD533 results in radiosensitization of human mammary carcinoma cells.
The inducible expression of dominant-negative epidermal growth factor receptor-CD533 results in radiosensitization of human mammary carcinoma cells.
复制标题
DOI：
--
复制
发表时间：
1999-02
期刊：
影响因子：
--
通讯作者：
J. Contessa;D. Reardon;D. Todd;P. Dent;Ross B. Mikkelsen;K. Valerie;G. Bowers;Rupert Schmidt-Ullrich
中科院分区：
文献类型：
--
作者：
J. Contessa;D. Reardon;D. Todd;P. Dent;Ross B. Mikkelsen;K. Valerie;G. Bowers;Rupert Schmidt-Ullrich
电离辐射激活表皮生长因子受体（EGFR）和涉及细胞保护性丝裂原活化蛋白激酶（MAPK）通路的下游信号传导。在我们研究EGFR在细胞对辐射反应中的作用的努力中，我们产生了乳腺癌细胞克隆MCF-TR 5-EGFR-CD 533和MDA-TR 15-EGFR-CD 533，其诱导表达EGFR-CD 533，EGFR-CD 533是一种缺乏促有丝分裂和转化活性的截短EGFR突变体。EGFR-CD 533表达抑制辐射和EGF诱导的EGFR自磷酸化和MAPK活化，因此，作为显性负突变体发挥作用，而不阻断EGFR或erbB-2（erbB受体Tyr激酶家族的另一个成员）的表达。EGFR-CD 533的表达仅最低限度地抑制细胞生长，并且不改变对单次辐射暴露的辐射敏感性。然而，在EGFR-CD 533表达的条件下，细胞重复2戈伊辐射暴露，基本上消除了它们随后细胞生长的能力。这些结果确定了通过基因操作抑制EGFR功能作为一种潜在的治疗策略。这种干预的概念是通过抵消辐射诱导的细胞保护性增殖反应来使细胞放射增敏。
Ionizing radiation activates the epidermal growth factor receptor (EGFR) and downstream signaling involving the cytoprotective mitogen-activated protein kinase (MAPK) pathway. In our effort to investigate the role of EGFR in cellular responses to radiation, we generated mammary carcinoma cell clones, MCF-TR5-EGFR-CD533 and MDA-TR15-EGFR-CD533, that inducibly express EGFR-CD533, a truncated EGFR mutant lacking mitogenic and transformation activity. EGFR-CD533 expression inhibits radiation- and EGF-induced EGFR autophosphorylation and MAPK activation and, therefore, functions as a dominant-negative mutant without blocking the expression of EGFR or erbB-2, another member of the erbB receptor Tyr kinase family. Expression of EGFR-CD533 only minimally inhibited cell growth and did not alter radiosensitivity to single radiation exposures. However, repeated 2 Gy radiation exposures of cells, under conditions of EGFR-CD533 expression, essentially abolished their ability for subsequent cell growth. These results identify the inhibition of EGFR function through genetic manipulation as a potential therapeutic maneuver. The concept of such an intervention would be the radiosensitization of cells by counteracting a radiation-induced cytoprotective proliferation response.