Transient inhibition of p53 homologs protects ovarian function from two distinct apoptotic pathways triggered by anticancer therapies

So Youn Kim, Devi M. Nair, Megan Romero, Vanida A. Serna, Anthony J. Koleske, Teresa K. Woodruff, Takeshi Kurita

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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 TAp63α 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 TAp63α through the ATR > CHEK1 pathway independent of TAp63α hyper-phosphorylation, whereas X-irradiation activates the ATM > CHEK2 > TAp63α-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.

Original languageEnglish (US)
Pages (from-to)502-515
Number of pages14
JournalCell Death and Differentiation
Volume26
Issue number3
DOIs
StatePublished - Mar 1 2019

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Oocytes
Phosphorylation
Apoptosis
Checkpoint Kinase 2
Phosphotransferases
X-Rays
Therapeutics
Ionizing Radiation
Platinum
Cisplatin
DNA Damage
Fertility
Drug Therapy

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Transient inhibition of p53 homologs protects ovarian function from two distinct apoptotic pathways triggered by anticancer therapies. / Kim, So Youn; Nair, Devi M.; Romero, Megan; Serna, Vanida A.; Koleske, Anthony J.; Woodruff, Teresa K.; Kurita, Takeshi.

In: Cell Death and Differentiation, Vol. 26, No. 3, 01.03.2019, p. 502-515.

Research output: Contribution to journalArticle

Kim, So Youn ; Nair, Devi M. ; Romero, Megan ; Serna, Vanida A. ; Koleske, Anthony J. ; Woodruff, Teresa K. ; Kurita, Takeshi. / Transient inhibition of p53 homologs protects ovarian function from two distinct apoptotic pathways triggered by anticancer therapies. In: Cell Death and Differentiation. 2019 ; Vol. 26, No. 3. pp. 502-515.
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