p53-dependent regulation of MDR1 gene expression causes selective resistance to chemotherapeutic agents
p53-dependent regulation of MDR1 gene expression causes selective resistance to chemotherapeutic agents
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DOI：
10.1073/pnas.94.20.11037
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发表时间：
1997-09-30
影响因子：
11.1
通讯作者：
Schuetz, JD
中科院分区：
文献类型：
--
作者：
Thottassery, JV;Zambetti, GP;Schuetz, JD
功能P53的缺失矛盾地导致对化疗药物耐药性的增加或减少。P53状态与药物敏感性之间的不一致关系可能反映了P53对化疗药物细胞毒反应重要基因的选择性调控。我们推测，P53对化疗细胞毒性的不同作用是由于P53对正常表达多药耐药基因(Mdr1)的肿瘤中多药耐药基因(Mdr1)表达的调节。为了验证野生型p53调控内源性mdr1基因的假说，我们将反式显性负性p53基因稳定地导入表达P-糖蛋白(Pgp)且具有野生型p53的啮齿动物H35肝癌细胞。在表达TdN P53的细胞中，Pgp和mdr1a的mRNA水平显著升高，并与这些细胞中P53功能受损(包括反式激活和反式抑制)有关。Mdr1a基因在TDNp53细胞中的表达增强并非继发于mdr1基因扩增，而长春花碱摄取减少证明Pgp具有功能。细胞毒实验表明，TDNP53细胞对Pgp底物选择性不敏感。Pgp抑制剂利血平恢复了敏感性，表明只有药物滞留是药物敏感性丧失的基础。类似的发现在人类LS180结肠癌细胞中也很明显，这些细胞被设计成过表达TDNP53。因此，肿瘤中出现的P53失活可能导致对化疗药物的选择性耐药，因为mdr1表达上调。
Loss of functional p53 paradoxically results in either increased or decreased resistance to chemotherapeutic drugs. The inconsistent relationship between p53 status and drug sensitivity may reflect p53's selective regulation of genes important to cytotoxic response of chemotherapeutic agents, We reasoned that the discrepant effects of p53 on chemotherapeutic cytotoxicity is due to p53-dependent regulation of the multidrug resistance gene (MDR1) expression in tumors that normally express MDR1, To test the hypothesis that wild-type p53 regulates the endogenous mdr1 gene we stably introduced a trans-dominant negative (TDN) p53 into rodent H35 hepatoma cells that express P-glycoprotein (Pgp) and have wild-type p53. Levels of Pgp and mdr1a mRNA were markedly elevated in cells expressing TDN p53 and were linked to impaired p53 function (both transactivation and transrepression) in these cells. Enhanced mdr1a gene expression in the TDN p53 cells was not secondary to mdr1 gene amplification and Pgp was functional as demonstrated by the decreased uptake of vinblastine. Cytotoxicity assays revealed that the TDN p53 cell lines were selectively insensitive to Pgp substrates. Sensitivity was restored by the Pgp inhibitor reserpine, demonstrating that only drug retention was the basis for loss of drug sensitivity. Similar findings were evident in human LS180 colon carcinoma cells engineered to overexpress TDN p53. Therefore, the p53 inactivation seen in cancers likely leads to selective resistance to chemotherapeutic agents because of up-regulation of MDR1 expression.