Department of Surgical Oncology, University of Illinois College of Medicine, Chicago, Illinois, USA.
Mol Cancer Ther. 2009 Oct;8(10):2947-58. doi: 10.1158/1535-7163.MCT-09-0444. Epub 2009 Oct 6.
We report that amino acids 50 to 77 of azurin (p28) preferentially enter the human breast cancer cell lines MCF-7, ZR-75-1, and T47D through a caveolin-mediated pathway. Although p28 enters p53 wild-type MCF-7 and the isogenic p53 dominant-negative MDD2 breast cancer cell lines, p28 only induces a G(2)-M-phase cell cycle arrest and apoptosis in MCF-7 cells. p28 exerts its antiproliferative activity by reducing proteasomal degradation of p53 through formation of a p28:p53 complex within a hydrophobic DNA-binding domain (amino acids 80-276), increasing p53 levels and DNA-binding activity. Subsequent elevation of the cyclin-dependent kinase inhibitors p21 and p27 reduces cyclin-dependent kinase 2 and cyclin A levels in a time-dependent manner in MCF-7 cells but not in MDD2 cells. These results suggest that p28 and similar peptides that significantly reduce proteasomal degradation of p53 by a MDM2-independent pathway(s) may provide a unique series of cytostatic and cytotoxic (apoptotic) chemotherapeutic agents.
我们报告称，天青蛋白（p28）的 50 到 77 个氨基酸优先通过网格蛋白介导的途径进入人乳腺癌细胞系 MCF-7、ZR-75-1 和 T47D。尽管 p28 进入 p53 野生型 MCF-7 和同基因 p53 显性负性 MDD2 乳腺癌细胞系，但 p28 仅在 MCF-7 细胞中诱导 G2-M 期细胞周期停滞和细胞凋亡。p28 通过在疏水性 DNA 结合域（氨基酸 80-276）内形成 p28:p53 复合物，减少 p53 的蛋白酶体降解，从而发挥其抗增殖活性，增加 p53 水平和 DNA 结合活性。随后，细胞周期蛋白依赖性激酶抑制剂 p21 和 p27 的升高以时间依赖性方式降低 MCF-7 细胞中细胞周期蛋白依赖性激酶 2 和细胞周期蛋白 A 的水平，但在 MDD2 细胞中则不然。这些结果表明，p28 和类似的肽通过 MDM2 非依赖性途径显著降低 p53 的蛋白酶体降解，可能提供一系列独特的细胞生长抑制剂和细胞毒性（凋亡）化疗药物。
