Cloning and characterization of a novel intracellular protein p48.2 that negatively regulates cell cycle progression
Cloning and characterization of a novel intracellular protein p48.2 that negatively regulates cell cycle progression
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负调控细胞周期进程的新型细胞内蛋白 p48.2 的克隆和表征
DOI：
10.1016/j.biocel.2009.04.022
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发表时间：
2009-11-01
影响因子：
4
通讯作者：
Liu，Li
中科院分区：
文献类型：
--
作者：
Yang，Fan;Xu，Yu-Ping;Liu，Li
1型神经纤维瘤病（NF 1）微缺失是人类染色体17q11.2上至少包含11个连续基因的大基因组缺失。到目前为止，这些基因的功能大多数仍然不确定。在这项研究中，我们报告了一个未知的细胞因子受体样分子（p48.2），这是经常删除的患者与1型和2型NF 1微缺失的神经纤维蛋白基因座。该基因全长1317个碱基，编码438个氨基酸的胞内蛋白。该基因随后根据其预测的分子量被命名为p48.2。在p48.2的Arg 176和Pro 261之间发现了典型的III型纤连蛋白（FNIII）结构域，其中在该结构域的C末端发现了回文Arg-Gly-Asp（RGD）重复序列加上推定的Trp-Ser-X-Trp-Ser（WSXWS）基序。p48.2 mRNA在许多肿瘤细胞系和正常人体组织中含量丰富，在一些新鲜分离的肺癌和白血病细胞中表达上调。有趣的是，p48.2在人胚肾293 T细胞中的过表达可显著引起G 0/G1期阻滞并阻止S期进入。相反，通过特异性siRNA抑制内源性p48.2基因表达显著减少G 0/G1群体。重要的是，p48.2的过表达可以显著上调而不是下调cyclin D1和cyclin D3的表达。我们进一步发现，细胞周期蛋白D1的表达的诱导是直接由于信号转导和转录激活因子3（STAT 3）的激活，但不依赖于RAS/丝裂原活化蛋白激酶（RAS/MAPK）信号通路。因此，p48.2可能代表了一种新型的细胞内蛋白，在G 0/G1期起负调节作用。
Neurofibromatosis type 1 (NF1) microdeletion is a large genomic deletion that embraces at least 11 continuous genes at human chromosome 17q11.2. To date, most of these genes’ functions still remain undefined. In this study, we report an unknown cytokine receptor like molecule (p48.2) that is frequently deleted in patients with type-1 and type-2 NF1 microdeletions in the neurofibromin locus. The cloned gene has 1317 base pair long that encodes a 438aa intracellular protein. The gene was subsequently named p48.2 based on its predicted molecular weight. A typical fibronectin type III (FNIII) domain was identified in p48.2 between Arg176and Pro261in which a palindromic Arg-Gly-Asp (RGD) repeat plus a putative Trp-Ser-X-Trp-Ser (WSXWS) motif were found at the domain's C-terminus. p48.2 mRNAs were abundant in many tumor cell lines and normal human tissues and up-regulated in some freshly isolated lung cancer and leukemia cells. Interestingly, over-expression of p48.2 in human embryo kidney 293T cells could significantly cause G0/G1 arrest and prevented S phase entry. In contrast, repressing endogenous p48.2 gene expression by specific siRNA markedly reduced G0/G1 population. Importantly, over-expression of p48.2 could significantly up-regulate rather than down-regulate cyclin D1 and cyclin D3 expressions. We further showed that the induction of cyclin D1 expression was directly due to the activation of signal transducers and activators of transcription 3 (STAT3), but was independent of RAS/mitogen-activated protein kinase (RAS/MAPK) signaling pathway. Thus, p48.2 may represent a novel type of intracellular protein functioning as a negative regulator at the G0/G1 phase.