免疫細胞癌變可導致各種白血病/淋巴癌的發(fā)生,，這些是人類常見的惡性腫瘤,。淋巴細胞和粒細胞等由于某些特殊原因發(fā)生變異而誘發(fā)細胞癌變，其中Bcr-Abl融合癌基因主要誘發(fā)了慢性粒細胞白血病（CML）和急性淋巴細胞白血病（ALL）,。Bcr-Abl癌蛋白介導細胞癌變的過程涉及多種信號轉導通路的分子調控，其中JAK/STAT是關鍵信號通路之一,。SOCS家族蛋白作為細胞因子信號通路的抑制因子,，能有效地調節(jié)JAK/STAT信號通路，從而維持人體免疫細胞的正常功能和生理平衡,。然而,，在Bcr-Abl介導的免疫細胞癌變過程中，SOCS蛋白的作用及其調節(jié)機制迄今尚不清楚,。
中國科學院微生物研究所陳吉龍研究員領導的病毒感染與腫瘤發(fā)生機理研究組在前期研究中,，揭示了小鼠白血病病毒（攜帶v-Abl癌基因）感染改變了免疫細胞關鍵信號通路的活性（Oncogene， 2010,， 29：3845-3853）。在此基礎上,，針對Bcr-Abl癌蛋白如何改變SOCS家族的負調控功能展開研究,。通過蛋白質互作和免疫共沉淀等技術，篩選發(fā)現了當Bcr-Abl表達時,，SOCS-1和SOCS-3具有較高的酪氨酸磷酸化水平,，且鑒定其主要的酪氨酸磷酸化位點分別是SOCS-1的Y155和Y204，SOCS-3的Y221,。研究合作者,、美國Rothman教授研究組在CML病人外周血白細胞中也發(fā)現了SOCS-1的酪氨酸磷酸化。陳吉龍研究組通過一系列生物化學,、分子生物學以及細胞生物學等實驗,，證實了Bcr-Abl介導的SOCS-1和SOCS-3酪氨酸磷酸化使其失去了負調節(jié)JAK激酶的功能，并在人白血病K562細胞中無法有效地抑制JAK2,、STAT5的活性,，使BCL-XL蛋白持續(xù)表達,，從而抑制了細胞的凋亡。應用小鼠致瘤模型,，進一步證明了SOCS-1和SOCS-3主要酪氨酸磷酸化位點的突變能顯著地抑制Bcr-Abl介導的腫瘤形成及細胞轉化,。
此項研究揭示了Bcr-Abl癌蛋白通過磷酸化SOCS-1和SOCS-3的酪氨酸殘基，使其失去了負調節(jié)JAK/STAT信號通路的功能,，闡明了Bcr-Abl誘導STAT5持續(xù)活化從而促進Bcr-Abl介導免疫細胞癌變的機理,。這些研究結果加深了人們對免疫細胞癌變機制的認識，為徹底闡明免疫細胞癌變的信號調控網絡提供了幫助,。該研究成果已在線發(fā)表在國際腫瘤免疫學刊物Neoplasia上,。
此項工作得到了國家“973”計劃和國家自然科學基金等支持。（生物谷Bioon.com）
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A requirement for SOCS-1 and SOCS-3 phosphorylation in Bcr-Abl-induced tumorigenesis
Xiaoxue Qiu, Guijie Guo, Ke Chen, Masaki Kashiwada, Brian Druker, Paul Rothman and Jilong Chen
SOCS-1 and SOCS-3 are inhibitors of JAK/STAT pathway and function in a negative feedback loop during cytokine signaling. Abl transformation is associated with constitutive activation of JAK/STAT-dependent signaling. However, the mechanism by which Abl oncoproteins bypass SOCS inhibitory regulation remains poorly defined. Here, we demonstrate that co-expression of Bcr-Abl with SOCS-1 or SOCS-3 results in tyrosine phosphorylation of these SOCS proteins. Interestingly, SOCS-1 is highly tyrosine phosphorylated in one of five primary CML samples. Bcr-Abl-dependent tyrosine phosphorylation of SOCS-1 and SOCS-3 occurs mainly on Tyr 155 and Tyr 204 residues of SOCS-1, and Tyr 221 residue of SOCS-3. We observed that phosphorylation of these SOCS proteins was associated with their binding to Bcr-Abl. Bcr-Abl-dependent phosphorylation of SOCS-1 and SOCS-3 diminished their inhibitory effects on the activation of JAK and STAT5 and thereby enhanced JAK/STAT5 signaling. Strikingly, disrupting the tyrosine phosphorylation of SOCS-1 or SOCS-3 impaired the expression of Bcl-XL protein and sensitized K562 leukemic cells to undergo apoptosis. Moreover, selective mutation of tyrosine phosphorylation sites of SOCS-1 or SOCS-3 significantly blocked Bcr-Abl-mediated tumorigenesis in nude mice and inhibited Bcr-Abl-mediated murine bone marrow transformation. Together, these results reveal a mechanism of how Bcr-Abl may overcome SOCS-1 and SOCS-3 inhibition to constitutively activate the JAK/STAT-dependent signaling, and suggest that Bcr-Abl may critically requires tyrosine phosphorylation of SOCS-1 and SOCS-3 to mediate tumorigenesis when these SOCS proteins are present in cells.
