PTHrP promotes development of mouse preimplantation embryos through the AKT/cyclin D1 pathway and nuclear translocation of HDAC4
PTHrP promotes development of mouse preimplantation embryos through the AKT/cyclin D1 pathway and nuclear translocation of HDAC4
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DOI：
10.1002/jcp.30362
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发表时间：
2021-03
影响因子：
5.6
通讯作者：
Yuan-Yuan Li-Yuan;Lei Guo;Hui Li;Wen-Long Lei;Li-Hua Fan;Yingchun Ouyang;Yi Hou;Zhenbo Wang;
中科院分区：
文献类型：
--
作者：
Yuan-Yuan Li-Yuan;Lei Guo;Hui Li;Wen-Long Lei;Li-Hua Fan;Yingchun Ouyang;Yi Hou;Zhenbo Wang;
甲状旁腺激素相关蛋白（PTHrP）是恶性肿瘤体液性高钙血症的主要原因，在胚胎发育过程中促进细胞增殖并延迟终末细胞成熟。我们的前期研究报道PTHrP在小鼠胚胎发育过程中对囊胚形成、多能性基因表达和组蛋白乙酰化起重要作用。本研究进一步探讨了PTHrP调控植入前胚胎发育的机制。我们的结果表明，Pthrp缺失降低了卵裂期胚胎的发育率和桑椹胚期胚胎的细胞数量。Pthrp缺失的胚胎细胞周期蛋白D1、磷酸化（p）-AKT（Thr 308）和E2 F1的水平显著降低。然而，Pthrp缺失并未引起CDK 4、β-连环蛋白或RUNX 2表达的显著变化。此外，我们的研究结果表明，Pthrp耗竭通过刺激蛋白磷酸酶2A（PP 2A）的活性促进HDAC 4从细胞质易位到卵裂期胚胎的细胞核，这导致HDAC 4的去磷酸化。总之，这些结果表明，PTHrP通过AKT/细胞周期蛋白D1途径调节卵裂分裂进程和囊胚形成，并且PTHrP通过小鼠植入前胚胎发育期间PP 2A依赖性HDAC 4去磷酸化的HDAC 4核转位调节组蛋白乙酰化模式。
Parathyroid hormone‐related protein (PTHrP), the main cause of humoral hypercalcemia in malignancies, promotes cell proliferation and delays terminal cell maturation during embryonic development. Our previous study reported that PTHrP plays important roles in blastocyst formation, pluripotency gene expression, and histone acetylation during mouse preimplantation embryonic development. In this study, we further investigated the mechanism of preimplantation embryonic development regulated by PTHrP. Our results showed that Pthrp depletion decreased both the developmental rate of embryos at the cleavage stage and the cell number of morula‐stage embryos. Pthrp‐depleted embryos had significantly decreased levels of cyclin D1, phospho (p)‐AKT (Thr308) and E2F1. However, Pthrp depletion did not cause significant changes in CDK4, β‐catenin or RUNX2 expression. In addition, our results indicated that Pthrp depletion promoted HDAC4 translocation from the cytoplasm to the nucleus in cleavage‐stage embryos by stimulating the activity of protein phosphatase 2A (PP2A), which resulted in dephosphorylation of HDAC4. Taken together, these results suggest that PTHrP regulates cleavage division progression and blastocyst formation through the AKT/cyclin D1 pathway and that PTHrP modulates histone acetylation patterns through nuclear translocation of HDAC4 via PP2A‐dependent HDAC4 dephosphorylation during preimplantation embryonic development in mice.