| First Author | Kim SY | Year | 2019 |
| Journal | Cell Death Differ | Volume | 26 |
| Issue | 3 | Pages | 502-515 |
| PubMed ID | 29988075 | Mgi Jnum | J:280257 |
| Mgi Id | MGI:6359132 | Doi | 10.1038/s41418-018-0151-2 |
| Citation | Kim SY, et al. (2019) Transient inhibition of p53 homologs protects ovarian function from two distinct apoptotic pathways triggered by anticancer therapies. Cell Death Differ 26(3):502-515 |
| abstractText | Platinum-based chemotherapies can result in ovarian insufficiency by reducing the ovarian reserve, a reduction believed to result from apoptosis of immature oocytes via activation/phosphorylation of TAp63alpha by multiple kinases including CHEK2, CK1, and ABL1. Here we demonstrate that cisplatin (CDDP) induces oocyte apoptosis through a novel pathway and that temporary repression of this pathway fully preserves ovarian function in vivo. Although ABL kinase inhibitors effectively block CDDP-induced apoptosis of oocytes, oocytic ABL1, and ABL2 are dispensable for damage-induced apoptosis. Instead, CDDP activates TAp63alpha through the ATR > CHEK1 pathway independent of TAp63alpha hyper-phosphorylation, whereas X-irradiation activates the ATM > CHEK2 > TAp63alpha-hyper-phosphorylation pathway. Furthermore, oocyte-specific deletion of Trp73 partially protects oocytes from CDDP but not from X-ray, highlighting the fundamental differences of two pathways. Nevertheless, temporary repression of DNA damage response by a kinase inhibitor that attenuates phosphorylation of ATM, ATR, CHEK1, and CHEK2 fully preserves fertility in female mice against CDDP as well as X-ray. Our current study establishes the molecular basis and feasibility of adjuvant therapies to protect ovarian function against two distinctive gonadotoxic therapeutics, CDDP, and ionizing radiation. |
