Elbendary A A, Cirisano F D, Evans A C, Davis P L, Iglehart J D, Marks J R, Berchuck A
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology and Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Clin Cancer Res. 1996 Sep;2(9):1571-5.
In many cell types, p53-mediated growth inhibition is dependent on induction of p21, which is an inhibitor of cyclin-dependent kinases that are required for cell cycle progression. Failure of mutant p53 proteins to transactivate p21 may lead to uncontrolled proliferation. Because many ovarian cancers have mutations in the p53 gene, we examined p21 levels in normal and malignant ovarian epithelial cells to determine whether p21 expression is dependent on wild-type p53. Normal ovarian epithelial cells and two ovarian cancer cell lines with wild-type p53 expressed readily detectable levels of p21, whereas in p53 null and mutant cell lines, expression of p21 was diminished strikingly. A correlation between the status of the p53 gene and p21 expression also was noted in 23 primary epithelial ovarian cancers. Normal levels of p21 RNA were seen in 4/7 (57%) cancers with wild-type p53, whereas 14/16 (88%) cancers with mutant p53 had reduced p21 expression (P < 0.05). In addition, we found that lambda-irradiation of normal and malignant ovarian epithelial cells with wild-type, but not mutant, p53 resulted in induction of p21. These data are suggestive that induction of p21 is a feature of p53-mediated growth inhibition in normal ovarian epithelial cells. Conversely, mutation of the p53 gene in ovarian cancers usually is associated with decreased p21 expression. The lack of an absolute correlation between p21 expression and the status of the p53 gene in ovarian cancers is consistent with other studies that have suggested that p21 may also be regulated by p53-independent pathways.
在许多细胞类型中，p53介导的生长抑制依赖于p21的诱导，p21是细胞周期进程所必需的细胞周期蛋白依赖性激酶的抑制剂。突变型p53蛋白无法反式激活p21可能导致不受控制的增殖。由于许多卵巢癌存在p53基因突变，我们检测了正常和恶性卵巢上皮细胞中的p21水平，以确定p21的表达是否依赖于野生型p53。正常卵巢上皮细胞和两个具有野生型p53的卵巢癌细胞系表达了易于检测到的p21水平，而在p53缺失和突变的细胞系中，p21的表达显著降低。在23例原发性上皮性卵巢癌中也发现了p53基因状态与p21表达之间的相关性。在7例具有野生型p53的癌症中，4例（57%）可见p21 RNA水平正常，而在16例具有突变型p53的癌症中，14例（88%）p21表达降低（P<0.05）。此外，我们发现，用野生型而非突变型p53对正常和恶性卵巢上皮细胞进行λ射线照射会导致p21的诱导。这些数据表明，p21的诱导是正常卵巢上皮细胞中p53介导的生长抑制的一个特征。相反，卵巢癌中p53基因的突变通常与p21表达降低有关。卵巢癌中p21表达与p53基因状态之间缺乏绝对相关性，这与其他研究一致，这些研究表明p21也可能受p53非依赖性途径调控。
