Almazov V P, Kochetkov D V, Chumakov P M
Mol Biol (Mosk). 2007 Nov-Dec;41(6):947-63.
Tumor suppressor p53 is the central component of a system maintaining the genetic stability of animal and human somatic cells. Its gene is inactivated in almost all human cancers, allowing a tumor cell to rapidly accumulate additional mutations and progress toward a more malignant phenotype. Yet tumor cells are most sensitive to the suppressor effect of p53 when its function is restored. Hence, restoration of the p53 function is an appealing strategy of anticancer therapy. Various mechanisms inactivate p53 in cancer, including point mutations resulting in synthesis of an inactive mutant protein, deletion of the total gene or its portion, damage to the genes involved in regulating the p53 activity, and defects in p53 target genes. In addition, oncogenic viruses code for the specialized proteins that modify the p53 function to ensure optimal replication of the virus genome. These viral proteins are crucial for virus-induced carcinogenesis, in particular, in 95% of cervical carcinoma cases in women. The approaches to p53 activity restoration depend to a great extent on the defect in p53-dependent signaling. Introduction of exogenous p53 is effective in some case and is usually achieved with adenoviral vectors. The approaches under study are aimed at restoring the activity of mutant p53 or suppressing the viral inhibitors of p53. The review considers various schemes involving p53 in cancer therapy and prevention and discusses their potential efficacy and prospects of their clinical use.
肿瘤抑制因子p53是维持动物和人类体细胞遗传稳定性系统的核心组成部分。其基因在几乎所有人类癌症中失活，使肿瘤细胞能够迅速积累额外的突变并发展为更恶性的表型。然而，当p53的功能恢复时，肿瘤细胞对其抑制作用最为敏感。因此，恢复p53功能是一种有吸引力的抗癌治疗策略。癌症中多种机制可使p53失活，包括导致无活性突变蛋白合成的点突变、整个基因或其部分的缺失、参与调节p53活性的基因受损以及p53靶基因的缺陷。此外，致癌病毒编码特殊蛋白质来改变p53功能，以确保病毒基因组的最佳复制。这些病毒蛋白对病毒诱导的致癌作用至关重要，尤其是在95%的女性宫颈癌病例中。恢复p53活性的方法在很大程度上取决于p53依赖性信号传导中的缺陷。在某些情况下，引入外源性p53是有效的，通常通过腺病毒载体来实现。正在研究的方法旨在恢复突变型p53的活性或抑制p53的病毒抑制剂。本文综述了癌症治疗和预防中涉及p53的各种方案，并讨论了它们的潜在疗效及临床应用前景。
