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首页> 外文期刊>Cell death and differentiation >p63 and p73 coordinate p53 function to determine the balance between survival, cell death, and senescence in adult neural precursor cells.
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p63 and p73 coordinate p53 function to determine the balance between survival, cell death, and senescence in adult neural precursor cells.

机译：p63和p73协调p53的功能，以确定成年神经前体细胞的存活，细胞死亡和衰老之间的平衡。

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The p53 family members p73 and p63 have been implicated in various aspects of stem cell regulation. Here, we have asked whether they work together to regulate stem cell biology, focusing upon neural precursor cells (NPCs) in the adult murine brain. By studying mice that are haploinsufficient for p63 and/or p73, we show that these two proteins cooperate to ensure appropriate NPC self-renewal and long-term maintenance in the hippocampus and forebrain, and that when both are haploinsufficient, the NPC deficits are significantly greater than haploinsufficiency for either alone. We show that, in the case of p63(+/-) mice, this decrease in adult NPCs is caused by enhanced apoptosis. However, when p73 is coincidently haploinsufficient, this rescues the enhanced apoptosis of p63(+/-) NPCs under both basal conditions and following genotoxic stress, instead causing increased cellular senescence. This increase in cellular senescence is likely due, at least in part, to increased levels of basal DNA damage and p53 activation, as genetic ablation of p53 completely rescues the senescence phenotype observed in p63(+/-); p73(+/-) mice. Thus, the presence of p73 determines whether p63(+/-) NPCs exhibit increased p53-dependent apoptosis or senescence. Together, these studies demonstrate that p63 and p73 cooperate to maintain adult NPC pools through regulation of p53 function; p63 antagonizes p53 to promote cellular survival, whereas p73 regulates self-renewal and p53-mediated apoptosis versus senescence.
机译：p53家族成员p73和p63与干细胞调节的各个方面有关。在这里，我们询问了它们是否共同调节干细胞生物学，重点研究成年鼠脑中的神经前体细胞（NPC）。通过研究p63和/或p73的单倍体不足的小鼠，我们显示这两种蛋白协同作用以确保海马和前脑中适当的NPC自我更新和长期维持，并且当两者均单倍不足时，NPC缺陷明显大于任何一个人的单倍剂量不足。我们显示，在p63（+/-）小鼠的情况下，这种成年NPC的减少是由凋亡增加引起的。但是，当p73恰好是单倍体不足时，这可以在基础条件和遗传毒性胁迫下挽救p63（+/-）NPC增强的凋亡，而不是引起细胞衰老。细胞衰老的这种增加可能至少部分是由于基础DNA损伤和p53活化水平的提高，因为p53的遗传消融完全拯救了p63（+/-）中观察到的衰老表型。 p73（+/-）小鼠。因此，p73的存在确定p63（+/-）NPC是否表现出增加的p53依赖性细胞凋亡或衰老。总之，这些研究表明p63和p73通过调节p53功能来维持成人NPC库。 p63拮抗p53以促进细胞存活，而p73调节自我更新和p53介导的细胞凋亡与衰老。

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