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磷酸脂酶 Cδ-4（PLCδ4）作为核内调控因子影响横纹肌肉瘤细胞系 RD 和 A204 中细胞周期蛋白 B 的表达。

Phospholipase Cδ-4 (PLCδ4) Acts as a Nuclear Player to Influence Cyclin B Expression in the Embryonal Rhabdomyosarcoma Cell Lines RD and A204.

机构信息

Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, 40126 Bologna, Italy.

Laboratory of Experimental Oncology, IRCCS, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.

出版信息

Biomolecules. 2024 Sep 20;14(9):1180. doi: 10.3390/biom14091180.

DOI:10.3390/biom14091180
PMID:39334946
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11430102/
Abstract

Rhabdomyosarcoma (RMS), the most common form of sarcoma typical of pediatric age, arises from the malignant transformation of the mesenchymal precursors that fail to differentiate into skeletal muscle cells. Here, we investigated whether the protein phospholipase C δ4 (PLCδ4), a member of the PLC family involved in proliferation and senescence mechanisms of mesenchymal stromal stem cells, may play a role in RMS. Our molecular and morpho-functional data reveal that PLCδ4 is highly expressed in the fusion-negative, p53-positive, SMARCB1 heterozygous mutated embryonal RMS (ERMS) cell line A204, while it is poorly expressed in the ERMS cell lines RD (fusion-negative, MYC amplification, N-RAS (Q61H), homozygous mutated p53) and Hs729 (homozygous mutated p53) and the alveolar rhabdosarcoma (ARMS) cell line SJCRH30 (RH30; fusion positive, heterozygous mutated RARA, polyheterozygous mutated p53). To characterize the role of PLCδ4, the RD cell line was stably transfected with wild-type PLCδ4 (RD/PLCδ4). Overexpressed PLCδ4 mainly localized to the nucleus in RD cells and contributed to the phosphorylation of PRAS40 (T246), Chk2(T68), WNK1(T60), and Akt 1/273 (S473), as revealed by proteome profiler array analysis. Overexpression of PLCδ4 in RD cells enhanced cyclin B1 expression and resulted in G2/M-phase cell cycle arrest. In contrast, siRNA-mediated knockdown of PLCδ4 in A204 cells resulted in reduced cyclin B1 expression. Our study identifies a novel role for nuclear PLCδ4 as a regulator of cyclin B1 via Akt-dependent phosphorylation. The modulation of PLCδ4 expression and its downstream targets could represent a crucial signaling pathway to block embryonal RMS cell proliferation.

摘要

横纹肌肉瘤 (RMS) 是小儿期最常见的肉瘤形式，源自间充质前体的恶性转化，这些前体未能分化成骨骼肌细胞。在这里，我们研究了蛋白磷脂酶 C δ4 (PLCδ4) 是否可能在 RMS 中发挥作用。PLCδ4 是 PLC 家族的成员，参与间充质基质干细胞的增殖和衰老机制，我们的分子和形态功能数据显示，PLCδ4 在融合阴性、p53 阳性、SMARCB1 杂合突变的胚胎性 RMS (ERMS) 细胞系 A204 中高度表达，而在 ERMS 细胞系 RD (融合阴性、MYC 扩增、N-RAS (Q61H)、纯合突变 p53) 和 Hs729 (纯合突变 p53) 以及肺泡横纹肌肉瘤 (ARMS) 细胞系 SJCRH30 (RH30; 融合阳性、杂合突变 RARA、多杂合突变 p53) 中表达水平较低。为了表征 PLCδ4 的作用，我们将 RD 细胞系稳定转染野生型 PLCδ4 (RD/PLCδ4)。在 RD 细胞中，过表达的 PLCδ4 主要定位于细胞核，并通过蛋白质组谱分析揭示其有助于 PRAS40 (T246)、Chk2(T68)、WNK1(T60) 和 Akt 1/273 (S473) 的磷酸化。RD 细胞中 PLCδ4 的过表达增强了细胞周期蛋白 B1 的表达，导致 G2/M 期细胞周期阻滞。相反，A204 细胞中 PLCδ4 的 siRNA 介导敲低导致细胞周期蛋白 B1 的表达减少。我们的研究确定了核 PLCδ4 作为通过 Akt 依赖性磷酸化调节细胞周期蛋白 B1 的新作用。PLCδ4 表达及其下游靶标的调节可能代表阻断胚胎性 RMS 细胞增殖的关键信号通路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/6dcad5ba1d15/biomolecules-14-01180-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/4221fd2d9842/biomolecules-14-01180-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/f0bcf4f7b767/biomolecules-14-01180-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/27fe842234d6/biomolecules-14-01180-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/f32d89f432c9/biomolecules-14-01180-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/9cc6b803d690/biomolecules-14-01180-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/5f6c8231d42d/biomolecules-14-01180-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/84daa9fcdee3/biomolecules-14-01180-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/6dcad5ba1d15/biomolecules-14-01180-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/4221fd2d9842/biomolecules-14-01180-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/f0bcf4f7b767/biomolecules-14-01180-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/27fe842234d6/biomolecules-14-01180-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/f32d89f432c9/biomolecules-14-01180-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/9cc6b803d690/biomolecules-14-01180-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/5f6c8231d42d/biomolecules-14-01180-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/84daa9fcdee3/biomolecules-14-01180-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc9f/11430102/6dcad5ba1d15/biomolecules-14-01180-g008.jpg

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