Reactivation of p53 gene by MDM2 inhibitors: A novel therapy for cancer treatment

被引:120
作者
Gupta, Amit [1 ]
Shah, Karan [2 ]
Oza, Manisha J. [3 ]
Behl, Tapan [4 ]
机构
[1] Indo Soviet Friendship Coll Pharm, Dept Pharmacol, Anim Tissue Culture Lab, Moga, Punjab, India
[2] Smt NHL Municipal Med Coll, Dept Pharmacol, Ahmadabad, Gujarat, India
[3] SVKMs Dr Bhanuben Nanavati Coll Pharm, Bombay, Maharashtra, India
[4] Chitkara Univ, Chitkara Coll Pharm, Dept Pharmacol, Rajpura, Punjab, India
关键词
Mutations; Negative regulator; E3 ubiquitin ligase; Ubiquitination; Antagonism; UBIQUITIN-PROTEIN LIGASE; P53-MEDIATED G(1) ARREST; TUMOR-SUPPRESSOR; CELLS; GROWTH; TARGET; DIFFERENTIATION; CHECKPOINTS; COMBINATION; ACTIVATION;
D O I
10.1016/j.biopha.2018.10.155
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Cancer is an uncontrolled and abnormal growth of cells in the body. Gene that guards the cell cycle and function as tumor suppressor is p53 (also called as the guardian of the genome) which is encoded by the TP53 gene. Various events like DNA damage, heat shock, hypoxia and oncogene over expression, results in activation of p53. Thus, it plays a major role as a regulatory protein which regulates various diverse biological responses, responsible for genetic stability by preventing genome mutation. More than 50% mutations in human cancers along with the increase in expression of murine double minute 2 gene (mdm2), has been found as one of the reason for cancer progression. Murine double minute 2 (MDM2) is the negative regulator of p53 gene forming an autoregulatory feedback loop controlling each other cellular levels. Murine double minute 2 is unique E3 ubiquitin ligase protein which is responsible for ubiquitination and degradation of p53 gene. Many drugs/compounds have been developed for reactivation of p53 gene by inhibiting MDM2 interaction with p53, using MDM2 antagonism, inhibiting E3 ubiquitination of p53. Many compounds have entered clinical trials in haematological malignancies. This review will throw some light on reactivation of p53 gene by MDM2 and its homologues.
引用
收藏
页码:484 / 492
页数:9
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