免疫細(xì)胞癌變可導(dǎo)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(xì)胞和粒細(xì)胞等由于某些特殊原因發(fā)生變異而誘發(fā)細(xì)胞癌變，其中Bcr-Abl融合癌基因主要誘發(fā)了慢性粒細(xì)胞白血?。–ML）和急性淋巴細(xì)胞白血?。ˋLL）。Bcr-Abl癌蛋白介導(dǎo)細(xì)胞癌變的過程涉及多種信號轉(zhuǎn)導(dǎo)通路的分子調(diào)控,，其中JAK/STAT是關(guān)鍵信號通路之一,。SOCS家族蛋白作為細(xì)胞因子信號通路的抑制因子，能有效地調(diào)節(jié)JAK/STAT信號通路,，從而維持人體免疫細(xì)胞的正常功能和生理平衡,。然而，在Bcr-Abl介導(dǎo)的免疫細(xì)胞癌變過程中,，SOCS蛋白的作用及其調(diào)節(jié)機(jī)制迄今尚不清楚,。
中國科學(xué)院微生物研究所陳吉龍研究員領(lǐng)導(dǎo)的病毒感染與腫瘤發(fā)生機(jī)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(xì)胞關(guān)鍵信號通路的活性（Oncogene,， 2010,， 29：3845-3853）。在此基礎(chǔ)上,，針對Bcr-Abl癌蛋白如何改變SOCS家族的負(fù)調(diào)控功能展開研究,。通過蛋白質(zhì)互作和免疫共沉淀等技術(shù),，篩選發(fā)現(xiàn)了當(dāng)Bcr-Abl表達(dá)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(xì)胞中也發(fā)現(xiàn)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(xué)、分子生物學(xué)以及細(xì)胞生物學(xué)等實驗,，證實了Bcr-Abl介導(dǎo)的SOCS-1和SOCS-3酪氨酸磷酸化使其失去了負(fù)調(diào)節(jié)JAK激酶的功能,，并在人白血病K562細(xì)胞中無法有效地抑制JAK2、STAT5的活性,，使BCL-XL蛋白持續(xù)表達(dá),，從而抑制了細(xì)胞的凋亡。應(yīng)用小鼠致瘤模型,，進(jìn)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(dǎo)的腫瘤形成及細(xì)胞轉(zhuǎn)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(fù)調(diào)節(jié)JAK/STAT信號通路的功能,，闡明了Bcr-Abl誘導(dǎo)STAT5持續(xù)活化從而促進(jìn)Bcr-Abl介導(dǎo)免疫細(xì)胞癌變的機(jī)理,。這些研究結(jié)果加深了人們對免疫細(xì)胞癌變機(jī)制的認(rèn)識，為徹底闡明免疫細(xì)胞癌變的信號調(diào)控網(wǎng)絡(luò)提供了幫助,。該研究成果已在線發(fā)表在國際腫瘤免疫學(xué)刊物Neoplasia上,。
此項工作得到了國家“973”計劃和國家自然科學(xué)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.
