p53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose phosphate pathway.
p53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose phosphate pathway.
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p53 通过抑制 PFKFB3 表达并促进戊糖磷酸途径来协调 DNA 修复和核苷酸合成。
DOI：
10.1038/srep38067
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发表时间：
2016-11-30
影响因子：
4.6
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Franklin DA;He Y;Leslie PL;Tikunov AP;Fenger N;Macdonald JM;Zhang Y
p53对DNA损伤的反应性激活对于肿瘤抑制是必不可少的。虽然以前的研究强调了p53依赖的细胞周期阻滞和细胞凋亡对肿瘤抑制的重要性，但最近的研究表明，p53调控的其他领域，如代谢和DNA损伤修复（DDR），对p53依赖的肿瘤抑制也是必不可少的。然而，p53介导的DDR和代谢调节之间的内在联系仍然不完全清楚。在这里，我们提出的数据表明，p53促进核苷酸的生物合成响应DNA损伤抑制表达的磷酸果糖激酶-2（PFK 2）亚型6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶3（PFKFB 3），限速酶，促进糖酵解。PFKFB 3抑制增加了葡萄糖通过磷酸戊糖途径（PPP）的流量，以增加核苷酸的产生，这导致更有效的DNA损伤修复和增加细胞存活。有趣的是，尽管p53介导的PFKFB 3抑制可以增加两种主要PPP产物NADPH和核苷酸，但只有核苷酸的产生是促进DDR所必需的。通过鉴定新的p53靶点PFKFB 3，我们报告了p53调节的代谢和DDR之间的重要机制联系，这两者在肿瘤抑制中发挥着至关重要的作用。
Activation of p53 in response to DNA damage is essential for tumor suppression. Although previous studies have emphasized the importance of p53-dependent cell cycle arrest and apoptosis for tumor suppression, recent studies have suggested that other areas of p53 regulation, such as metabolism and DNA damage repair (DDR), are also essential for p53-dependent tumor suppression. However, the intrinsic connections between p53-mediated DDR and metabolic regulation remain incompletely understood. Here, we present data suggesting that p53 promotes nucleotide biosynthesis in response to DNA damage by repressing the expression of the phosphofructokinase-2 (PFK2) isoform 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a rate-limiting enzyme that promotes glycolysis. PFKFB3 suppression increases the flux of glucose through the pentose phosphate pathway (PPP) to increase nucleotide production, which results in more efficient DNA damage repair and increased cell survival. Interestingly, although p53-mediated suppression of PFKFB3 could increase the two major PPP products, NADPH and nucleotides, only nucleotide production was essential to promote DDR. By identifying the novel p53 target PFKFB3, we report an important mechanistic connection between p53-regulated metabolism and DDR, both of which play crucial roles in tumor suppression.
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影响因子：
12.4
作者：
通讯作者：
--
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
DOI：
10.1038/nrd4003
发表时间：
2013-07
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.202485699
发表时间：
2002-10-01
影响因子：
11.1
作者：
Adimoolam, S;Ford, JM
通讯作者：
Ford, JM
影响因子：
30.8
作者：
Ciriello, Giovanni;Miller, Martin L.;Aksoy, Buelent Arman;Senbabaoglu, Yasin;Schultz, Nikolaus;Sander, Chris
通讯作者：
Sander, Chris