WIP1 is a novel specific target for growth hormone action.

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Publication Year:
2023
Authors:
Tugce Apaydin, Svetlana Zonis, Cuiqi Zhou, Christian Wong Valencia, Robert Barrett, Ger J Strous, Jan A Mol, Vera Chesnokova, Shlomo Melmed
PubMed ID:
37876819
Funding Grants:
Public Summary:
DNA in our cells can get damaged, and our bodies have repair systems to fix it. A key part of this repair process involves a protein called ATM and others that work with it. This study found that growth hormone (GH) can interfere with DNA repair by causing a protein called WIP1 to increase. WIP1 then turns off ATM and related repair proteins, leading to more DNA damage in cells. The researchers showed this effect in human colon cells, lab-grown mini-intestines, and mice. They also saw increased WIP1 in blood cells from patients who had high GH levels due to a tumor. Mice without the GH receptor had less WIP1 in their colon. When they blocked WIP1, the DNA repair process got back to normal, and the DNA damage caused by GH was reduced. They also discovered the detailed steps of how GH signals the cell to increase WIP1.
Scientific Abstract:
DNA damage repair (DDR) is mediated by phosphorylating effectors ATM kinase, CHK2, p53, and gammaH2AX. 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 gammaH2AX. 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.