Gain of Cellular Adaptation Due to Prolonged p53 Impairment Leads to Functional Switchover from p53 to p73 during DNA Damage in Acute Myeloid Leukemia Cells
Gain of Cellular Adaptation Due to Prolonged p53 Impairment Leads to Functional Switchover from p53 to p73 during DNA Damage in Acute Myeloid Leukemia Cells
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DOI：
10.1074/jbc.m110.122705
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发表时间：
2010-10-22
影响因子：
4.8
通讯作者：
Sa, Gaurisankar
中科院分区：
文献类型：
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作者：
Chakraborty, Juni;Banerjee, Shuvomoy;Sa, Gaurisankar
肿瘤抑制因子p53在调节细胞凋亡中起着重要作用。从进化的角度来看，p53的活性必须得到其他蛋白质的支持，以防这种蛋白质的任何功能受损，从而引发癌细胞中DNA损伤诱导的凋亡。我们采用多种实验方法来证明，在p53受损的癌细胞中，DNA损伤导致p53通过Chk-1与p73结合，这强烈影响Bax表达和p53非依赖性凋亡。相反，当p53功能恢复异位表达，Chk-2诱导p53积累，反过来盖过p73活性，这表明p53家族成员之间的拮抗相互作用。为了更好地理解这种相互作用，p53表达细胞的p53活性差异受损。在表达野生型p53的癌细胞中，p53沉默了几代，p73被激活，而当p53瞬时沉默时，没有观察到这种趋势。因此，即使在功能性p53设置中，延长的p53干扰也会导致"细胞适应的获得"，其方式是通过改变p73调节蛋白，例如Chk1激活和显性负性p73下调，改变细胞微环境以有利于p73激活。这些发现不仅揭示了一个迄今无法解释的机制，潜在的p53到p73的功能性突变，但也验证了p73作为一个有前途的和潜在的目标，在癌症治疗的功能性p53的情况下。
Tumor suppressor p53 plays the central role in regulating apoptosis in response to genotoxic stress. From an evolutionary perspective, the activity of p53 has to be backed up by other protein( s) in case of any functional impairment of this protein, to trigger DNA damage-induced apoptosis in cancer cells. We adopted multiple experimental approaches to demonstrate that in p53-impaired cancer cells, DNA damage caused accumulation of p53 paralogue p73 via Chk-1 that strongly impacted Bax expression and p53-independent apoptosis. On the contrary, when p53 function was restored by ectopic expression, Chk-2 induced p53 accumulation that in turn overshadowed p73 activity, suggesting an antagonistic interaction between p53 family members. To understand such interaction better, p53-expressing cells were impaired differentially for p53 activity. In wildtype p53-expressing cancer cells that were silenced for p53 for several generations, p73 was activated, whereas no such trend was observed when p53 was transiently silenced. Prolonged p53 interference, even in functional p53 settings, therefore, leads to the "gain of cellular adaptation" in a way that alters the cellular microenvironment in favor of p73 activation by altering p73-regulatory proteins, e.g. Chk1 activation and dominant negative p73 down-regulation. These findings not only unveil a hitherto unexplained mechanism underlying the functional switchover from p53 to p73, but also validate p73 as a promising and potential target for cancer therapy in the absence of functional p53.