TAp63 determines the fate of oocytes against DNA damage.
TAp63 determines the fate of oocytes against DNA damage.
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DOI：
10.1126/sciadv.ade1846
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发表时间：
2022-12-21
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
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环磷酰胺和多柔比星作为脱靶效应导致卵巢功能不全。然而，它们的卵母细胞死亡途径一直存在争议。在此，我们阐明了环磷酰胺和阿霉素诱导卵巢耗竭的确切机制。具有高PI 3 K活性的休眠卵母细胞对环磷酰胺的敏感性高于激活卵母细胞。检查点激酶2（CHK 2）抑制剂而不是GNF 2保护卵母细胞免受环磷酰胺和阿霉素的影响，因为环磷酰胺上调了p-CHK 2，并耗尽了RP 1基因敲除小鼠的原始卵泡。与以前的报道相反，TAp 63在环磷酰胺和阿霉素诱导的卵母细胞死亡中起关键作用。卵母细胞特异性Trp 63基因敲除小鼠可防止原始卵泡丢失，并维持环磷酰胺和多柔比星的生殖功能，这一点通过检测不到的BAX和cPARP水平表示。在这里，我们证明了TAp 63是决定卵母细胞死亡对DNA损伤的信号转导的基础。这项研究确定了TAp 63作为辅助治疗的靶分子的作用，以保护卵巢储备免受不同类型的化疗的影响。了解每个化疗药物的特定卵母细胞死亡途径将有助于开发针对它的生育保护剂。
Cyclophosphamide and doxorubicin lead to premature ovarian insufficiency as an off-target effect. However, their oocyte death pathway has been debated. Here, we clarified the precise mechanism of ovarian depletion induced by cyclophosphamide and doxorubicin. Dormant oocytes instead of activated oocytes with high PI3K activity were more sensitive to cyclophosphamide. Checkpoint kinase 2 (CHK2) inhibitor rather than GNF2 protected oocytes from cyclophosphamide and doxorubicin, as cyclophosphamide up-regulated p-CHK2 and depleted primordial follicles in Abl1 knockout mice. Contrary to previous reports, TAp63 is pivotal in cyclophosphamide and doxorubicin-induced oocyte death. Oocyte-specific Trp63 knockout mice prevented primordial follicle loss and maintained reproductive function from cyclophosphamide and doxorubicin, indicated by undetectable levels of BAX and cPARP. Here, we demonstrated that TAp63 is fundamental in determining the signaling of oocyte death against DNA damage. This study establishes the role of TAp63 as a target molecule of adjuvant therapies to protect the ovarian reserve from different classes of chemotherapy. Understanding the specific oocyte death pathway by each chemotherapeutic agent will help develop fertoprotectants against it.
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影响因子：
64.5
作者：
Deutsch GB;Zielonka EM;Coutandin D;Weber TA;Schäfer B;Hannewald J;Luh LM;Durst FG;Ibrahim M;Hoffmann J;Niesen FH;Sentürk A;Kunkel H;Brutschy B;Schleiff E;Knapp S;Acker-Palmer A;Grez M;McKeon F;Dötsch V
通讯作者：
Dötsch V
影响因子：
9
作者：
Bildik, Gamze;Acilan, Ceyda;Oktem, Ozgur
通讯作者：
Oktem, Ozgur
影响因子：
16
作者：
Kerr, Jeffrey B.;Hutt, Karla J.;Michalak, Ewa M.;Cook, Michele;Vandenberg, Cassandra J.;Liew, Seng H.;Bouillet, Philippe;Mills, Alea;Scott, Clare L.;Findlay, Jock K.;Strasser, Andreas
通讯作者：
Strasser, Andreas
影响因子：
--
作者：
Kim, So-Youn;Cho, Geum Joon;Davis, John S
通讯作者：
Davis, John S
DOI：
10.1007/978-3-030-43032-0_15
发表时间：
2020-01-01
期刊：
CURRENT ADVANCES IN OSTEOSARCOMA: CLINICAL PERSPECTIVES: PAST, PRESENT AND FUTURE, 2ND EDITION
影响因子：
--
作者：
Bhagat, Anchit;Kleinerman, Eugenie S.
通讯作者：
Kleinerman, Eugenie S.