WIP1 is a novel specific target for growth hormone action.
WIP1 is a novel specific target for growth hormone action.
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DOI：
10.1016/j.isci.2023.108117
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发表时间：
2023-11-17
期刊：
影响因子：
5.8
通讯作者：
Melmed, Shlomo
中科院分区：
文献类型：
--
作者：
Apaydin, Tugce;Zonis, Svetlana;Zhou, Cuiqi;Valencia, Christian Wong;Barrett, Robert;Strous, Ger J.;Mol, Jan A.;Chesnokova, Vera;Melmed, Shlomo
DNA损伤修复（DDR）由磷酸化效应物ATM激酶、CHK 2、p53和γ H2 AX介导。我们先前表明GH通过抑制pATM抑制DDR，导致DNA损伤累积。在这里，我们显示GH通过GH受体（GHR）诱导野生型p53诱导型磷酸酶1（WIP 1）发挥作用，该磷酸酶1使正常人结肠细胞和三维人肠类器官中的ATM及其效应物去磷酸化。携带GH分泌性异种移植物的小鼠表现出诱导的结肠WIP 1和抑制的pATM和γ H2 AX。WIP 1也在生长激素腺瘤GH升高患者的血沉棕黄层中诱导。相反，在GHR−/−小鼠中观察到结肠WIP 1减少。WIP 1抑制恢复ATM磷酸化和逆转GH诱导的DNA损伤。我们阐明了一个新的GH信号通路激活Src/AMPK触发HIPK 2核质迁移和抑制WIP 1泛素化。一致地，阻断AMPK或Src废除GH诱导的WIP 1。我们确定WIP 1作为GH介导的上皮DNA损伤积累的特异性靶点。磷酸酶WIP 1是一种新发现的上皮生长激素作用靶点。生长激素通过诱导WIP 1抑制DNA损伤反应途径。生长激素通过Src/AMPK/HIPK 2作用，增强WIP 1的稳定性。生长激素/WIP 1作用导致未修复的DNA损伤积累。生物化学;生理学;分子生物学
DNA damage repair (DDR) is mediated by phosphorylating effectors ATM kinase, CHK2, p53, and γH2AX. We showed earlier that GH suppresses DDR by suppressing pATM, resulting in DNA damage accumulation. Here, we show GH acting through GH receptor (GHR) inducing wild-type p53-inducible phosphatase 1 (WIP1), which dephosphorylated ATM and its effectors in normal human colon cells and three-dimensional human intestinal organoids. Mice bearing GH-secreting xenografts exhibited induced colon WIP1 with suppressed pATM and γH2AX. WIP1 was also induced in buffy coats derived from patients with elevated GH from somatotroph adenomas. In contrast, decreased colon WIP1 was observed in GHR−/− mice. WIP1 inhibition restored ATM phosphorylation and reversed GH-induced DNA damage. We elucidated a novel GH signaling pathway activating Src/AMPK to trigger HIPK2 nuclear-cytoplasmic relocation and suppressing WIP1 ubiquitination. Concordantly, blocking either AMPK or Src abolished GH-induced WIP1. We identify WIP1 as a specific target for GH-mediated epithelial DNA damage accumulation. Phosphatase WIP1 is a newly described target for epithelial GH action GH suppresses DNA damage response pathway by inducing WIP1 GH acts through Src/AMPK/HIPK2, enhancing WIP1 stability GH/WIP1 action results in unrepaired DNA damage accumulation Biochemistry; Physiology; Molecular biology
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
8.8
作者：
Chesnokova V;Zonis S;Apostolou A;Estrada HQ;Knott S;Wawrowsky K;Michelsen K;Ben-Shlomo A;Barrett R;Gorbunova V;Karalis K;Melmed S
通讯作者：
Melmed S
DOI：
10.20945/2359-3997000000186
发表时间：
2019-11-01
期刊：
Archives of Endocrinology and Metabolism
影响因子：
--
作者：
Chesnokova, Vera;Melmed, Shlomo
通讯作者：
Melmed, Shlomo
DOI：
10.1073/pnas.94.12.6048
发表时间：
1997-06-10
影响因子：
11.1
作者：
Fiscella, M;Zhang, HL;Appella, E
通讯作者：
Appella, E
影响因子：
1.4
作者：
Bayram, Fahri;Bitgen, Nazmiye;Baskol, Gulden
通讯作者：
Baskol, Gulden