PI3K-mediated PDGFRα signaling regulates survival and proliferation in skeletal development through p53-dependent intracellular pathways.
PI3K-mediated PDGFRα signaling regulates survival and proliferation in skeletal development through p53-dependent intracellular pathways.
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DOI：
10.1101/gad.238709.114
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发表时间：
2014-05-01
影响因子：
10.5
通讯作者：
Soriano P
中科院分区：
文献类型：
--
作者：
Fantauzzo KA;Soriano P
PI 3 K是小鼠骨骼发育过程中PDGFRα信号传导的主要下游效应物。Fantauzzo等人发现了胚胎中的骨骼缺陷，其中PDGFRα无法结合PI 3 K。他们鉴定了56种在PI 3 K介导的PDGFRα信号转导下游被Akt磷酸化的蛋白质。这些蛋白质中的几种，包括Ybox 1，通过调节p53介导细胞存活。这些发现将p53鉴定为PI 3 K参与的PDGFRα信号传导下游的新型效应子，其在体内骨骼发育期间调节存活和增殖。先前的研究已经确定磷脂酰肌醇3-激酶（PI 3 K）是小鼠骨骼发育过程中PDGFRα信号传导的主要下游效应物。PDGFRα不能结合PI 3 K（PdgfraPI 3 K/PI 3 K）的自磷酸化突变敲入胚胎表现出影响腭架、肩带、椎骨和胸骨的骨骼缺陷。为了鉴定PI 3 K介导的PDGFRα信号转导下游Akt磷酸化的蛋白质，我们从PDGF-AA处理的原代小鼠胚胎腭间充质（MEPM）裂解物中免疫沉淀Akt磷酸化底物，并通过纳米液相色谱串联质谱（nano-LC-MS/MS）分析肽。我们的分析产生了56种蛋白质的列表，其中包括10种调节细胞存活和增殖的蛋白质。我们证明，MEPM细胞存活受损的PI 3 K抑制剂的存在下，PdgfraPI 3 K/PI 3 K衍生的MEPM不增殖响应PDGF-AA治疗。几个确定的Akt磷酸化靶点，包括Ybox 1，通过调节p53介导细胞存活。我们发现，Ybox 1结合Trp 53启动子和p53蛋白，并且在MEPMs中PDGF-AA处理后Trp 53的表达显著降低。最后，我们证明了引入Trp 53无效等位基因可以减轻PdgfraPI 3 K/PI 3 K新生儿中发现的椎骨缺陷。我们的研究结果确定p53是PI 3 K参与的PDGFRα信号转导下游的一种新型效应子，可调节体内骨骼发育期间的存活和增殖。
PI3K is the main downstream effector of PDGFRα signaling during murine skeletal development. Fantauzzo et al. discovered skeletal defects in embryos in which PDGFRα is unable to bind PI3K. They identified 56 proteins that are phosphorylated by Akt downstream from PI3K-mediated PDGFRα signaling. Several of these proteins, including Ybox1, mediate cell survival through regulation of p53. These findings identify p53 as a novel effector downstream from PI3K-engaged PDGFRα signaling that regulates survival and proliferation during skeletal development in vivo. Previous studies have identified phosphatidylinositol 3-kinase (PI3K) as the main downstream effector of PDGFRα signaling during murine skeletal development. Autophosphorylation mutant knock-in embryos in which PDGFRα is unable to bind PI3K (PdgfraPI3K/PI3K) exhibit skeletal defects affecting the palatal shelves, shoulder girdle, vertebrae, and sternum. To identify proteins phosphorylated by Akt downstream from PI3K-mediated PDGFRα signaling, we immunoprecipitated Akt phosphorylation substrates from PDGF-AA-treated primary mouse embryonic palatal mesenchyme (MEPM) lysates and analyzed the peptides by nanoliquid chromatography coupled to tandem mass spectrometry (nano-LC-MS/MS). Our analysis generated a list of 56 proteins, including 10 that regulate cell survival and proliferation. We demonstrate that MEPM cell survival is impaired in the presence of a PI3K inhibitor and that PdgfraPI3K/PI3K-derived MEPMs do not proliferate in response to PDGF-AA treatment. Several of the identified Akt phosphorylation targets, including Ybox1, mediate cell survival through regulation of p53. We show that Ybox1 binds both the Trp53 promoter and the p53 protein and that expression of Trp53 is significantly decreased upon PDGF-AA treatment in MEPMs. Finally, we demonstrate that introduction of a Trp53-null allele attenuates the vertebral defects found in PdgfraPI3K/PI3K neonates. Our findings identify p53 as a novel effector downstream from PI3K-engaged PDGFRα signaling that regulates survival and proliferation during skeletal development in vivo.
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影响因子：
30.8
作者：
Ding, H;Wu, XL;Nagy, A
通讯作者：
Nagy, A
DOI：
10.1073/pnas.0603730103
发表时间：
2006-09-05
影响因子：
11.1
作者：
Dixon, Jill;Jones, Natalie C.;Trainor, Paul A.
通讯作者：
Trainor, Paul A.
影响因子：
5.3
作者：
Hamilton, TG;Klinghoffer, RA;Soriano, P
通讯作者：
Soriano, P
影响因子：
82.9
作者：
Jones, Natalie C.;Lynn, Megan L.;Trainor, Paul A.
通讯作者：
Trainor, Paul A.
影响因子：
14.9
作者：
Kerrien S;Aranda B;Breuza L;Bridge A;Broackes-Carter F;Chen C;Duesbury M;Dumousseau M;Feuermann M;Hinz U;Jandrasits C;Jimenez RC;Khadake J;Mahadevan U;Masson P;Pedruzzi I;Pfeiffenberger E;Porras P;Raghunath A;Roechert B;Orchard S;Hermjakob H
通讯作者：
Hermjakob H