Alli E, Yang J-M, Hait W N
Department of Pharmacology, The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
Oncogene. 2007 Feb 15;26(7):1003-12. doi: 10.1038/sj.onc.1209864. Epub 2006 Aug 14.
Cancers harboring dominant-negative p53 mutations are often aggressive and difficult to treat. Direct attempts to restore wild-type p53 function have produced little clinical benefit. We investigated whether targeting a p53-target gene could induce certain tumor-suppressor characteristics. We found that inhibition of stathmin, a microtubule regulator that can be transcriptionally repressed by wild-type p53, restored certain wild-type functions to cancer cells with mutant p53. Silencing of stathmin by small interfering RNA (siRNA) in mutant p53 cell lines lowered expression to that observed following activation of wild-type p53 by DNA damage in wild-type p53 cell lines. siRNA-induced repression of stathmin decreased cell proliferation, viability and clonogenicity in mutant p53 cell lines. Furthermore, knockdown of stathmin partially restored cell-cycle regulation and activation of apoptosis. Therefore, targeting stathmin, a gene product that is overexpressed in the presence of mutant p53, may represent a novel approach to treating cancers with aberrant p53 function.
携带显性负性p53突变的癌症通常具有侵袭性且难以治疗。直接尝试恢复野生型p53功能几乎没有产生临床益处。我们研究了靶向p53靶基因是否能诱导某些肿瘤抑制特性。我们发现抑制stathmin（一种可被野生型p53转录抑制的微管调节蛋白）能使具有突变p53的癌细胞恢复某些野生型功能。在突变p53细胞系中，通过小干扰RNA（siRNA）使stathmin沉默，可将其表达降低至野生型p53细胞系中DNA损伤激活野生型p53后所观察到的水平。siRNA诱导的stathmin抑制降低了突变p53细胞系中的细胞增殖、活力和克隆形成能力。此外，stathmin的敲低部分恢复了细胞周期调控和凋亡激活。因此，靶向stathmin（一种在存在突变p53时过度表达的基因产物）可能代表一种治疗p53功能异常癌症的新方法。
