Regulator of differentiation 1 (ROD1) binds to the amphipathic C-terminal peptide of thrombospondin-4 and is involved in its mitogenic activity.

Sadvakassova G; Dobocan MC; Difalco MR

摘要

The matrix protein thrombospondin-4 has an acidic amphipathic C-terminal peptide (C21) which stimulates erythroid cell proliferation. Here we show that C21 stimulates red cell formation in anemic mice in vivo. In vitro experiments indicated that the peptide-mediated increase of erythroid colony formation in cultures of human CD34+ hematopoietic progenitor cells was possible only under continuous presence of erythropoietin. In the absence of this cytokine, C21 stimulated exclusively myeloid colony formation. Therefore, the peptide is not a specific erythroid differentiation factor. In fact, it is mitogenic in non-erythroid cells, such as skin fibroblasts and kidney epithelial cells. In erythroleukemic TF-1 cells, it actually decreased the production of the erythroid differentiation marker glycophorin A. C21-affinity chromatography revealed regulator of differentiation 1 (ROD1) as a major C21-binding protein. ROD1 is the hematopoietic cell paralog of polypyrimidine tract binding proteins (PTBs), RNA splice regulators which regulate differentiation by repressing tissue-specific exons. ROD1 binding to C21 was strongly inhibited by synthetic RNAs in the order poly A > poly U > poly G = poly C and was weakly inhibited by a synthetic phosphorylated peptide mimicking the C-terminal domain of RNA polymerase II. Cellular overexpression or knockdown experiments of ROD1 suggest a role for this protein in the mitogenic activity of C21. Since the nuclear proteins ROD1 and PTBs regulate differentiation at a posttranscriptional level and there is a fast nuclear uptake of C21, we put forward the idea that the peptide is internalized, goes to the nucleus and maintains cells in a proliferative state by supporting ROD1-mediated inhibition of differentiation.

机译：矩阵蛋白thrombospondin-4具有酸性两性分子的c端肽(C21)刺激红细胞细胞增殖。表明,C21刺激红细胞形成贫血小鼠体内。表明,peptide-mediated增加的红细胞集落形成人类的文化CD34 +造血祖细胞是可能的只有在连续促红细胞生成素的存在。在缺乏这种细胞因子,C21刺激只粒细胞集落形成。肽不是特定的红细胞分化的因素。在non-erythroid细胞,如皮肤成纤维细胞和肾脏上皮细胞。TF-1细胞,它实际上减少了生产红细胞分化的标志血型糖蛋白a C21-affinity色谱法揭示了监管机构的区别1 (ROD1)一个主要C21-binding蛋白质。造血细胞polypyrimidine假字束结合蛋白(肺结核),RNA拼接监管机构调节分化的抑制组织外显子。通过合成rna C21强烈抑制订单多聚腺苷酸>聚U >聚保利C和G =被一个弱抑制合成磷酸化肽模仿c端域的RNA聚合酶II。过度或ROD1击倒的实验建议这种蛋白质在促有丝分裂的作用C21的活动。和肺结核调节分化转录后的水平和快速C21核吸收,我们提出了这个想法肽是内化,去核和维持细胞增殖通过支持ROD1-mediated抑制状态分化。

Regulator of differentiation 1 (ROD1) binds to the amphipathic C-terminal peptide of thrombospondin-4 and is involved in its mitogenic activity.

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