糖原合成酶激酶-3（glycogen synthase kinase-3，GSK-3）是一種多功能的絲氨酸/蘇氨酸蛋白激酶,，是細(xì)胞內(nèi)多種信號(hào)轉(zhuǎn)導(dǎo)通路中的重要成分,，不僅參與細(xì)胞內(nèi)糖代謝過(guò)程而且還參與細(xì)胞增殖、細(xì)胞分化和細(xì)胞凋亡等多種重要生理過(guò)程,。
GSK-3活性受多種機(jī)制調(diào)節(jié),，其活性調(diào)節(jié)異常時(shí)可引起多種重大疾病如糖尿病、神經(jīng)退行性疾病和腫瘤等,。GSK-3已成為許多疾病治療靶點(diǎn),，目前針對(duì)GSK-3靶點(diǎn)開發(fā)的抑制劑主要是ATP競(jìng)爭(zhēng)性的小分子GSK-3抑制劑。
GSK-3存在兩種異構(gòu)體,，GSK-3α和GSK-3β,，這兩種亞型具有一些相似的功能，但也發(fā)揮不同的角色,，這取決于細(xì)胞發(fā)展?fàn)顟B(tài),。近日，Molecular Cancer Research雜志上刊登的一則研究中,，研究人員發(fā)現(xiàn)GSK-3能促進(jìn)黑色素瘤細(xì)胞的生長(zhǎng)和生存,，用小分子抑制劑SB216763或基因特異性siRNA降低GSK-3表達(dá)后，黑色素瘤細(xì)胞的增殖降低,，細(xì)胞凋亡增加,，同時(shí)細(xì)胞形態(tài)也發(fā)生改變。
上述這些變化與黑色素瘤細(xì)胞PAX3的缺失呈正相關(guān)性,，PAX3是一種轉(zhuǎn)錄因子,，在黑素細(xì)胞的增殖、存活和遷移中發(fā)揮作用,。進(jìn)一步體外研究發(fā)現(xiàn),，PAX3能與GSK-3β殘基直接互動(dòng)，并被磷酸化,。在黑色素瘤細(xì)胞中,，直接抑制PAX3導(dǎo)致類似的黑色素瘤細(xì)胞增殖凋亡上的變化，這種變化與抑制GSK-3所帶來(lái)的效應(yīng)是類似的,。維持住PAX3的表達(dá)能保護(hù)黑色素細(xì)胞免受SB216763的抗腫瘤作用,。
這些數(shù)據(jù)證實(shí)GSK-3通過(guò)調(diào)控PAX3的磷酸化，提高PAX3表達(dá)水平影響黑色素瘤細(xì)胞的增殖和形態(tài),。（生物谷：Bioon.com）
doi:10.1158/1541-7786.MCR-11-0387
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Glycogen Synthase Kinase-3 promotes cell survival, growth and PAX3 levels in human melanoma cells
Jennifer D Kubic, Joseph B Mascarenhas, Takumi Iizuka, Don Wolfgeher, and Deborah Lang*
Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase involved in a diverse range of cellular processes. GSK-3 exists in two isoforms, GSK-3α and GSK-3β, which possess some functional redundancy but also play distinct roles depending on developmental and cellular context. In this report we found that GSK-3 actively promoted cell growth and survival in melanoma cells, and blocking this activity with small molecule inhibitor SB216763 or gene-specific siRNA decreased proliferation, increased apoptosis and altered cellular morphology. These alterations coincided with loss of PAX3, a transcription factor implicated in proliferation, survival and migration of developing melanoblasts. We further found that PAX3 directly interacted with and was phosphorylated in vitro on a number of residues by GSK-3β. In melanoma cells, direct inhibition of PAX3 lead to cellular changes that paralleled the response to GSK-3 inhibition. Maintenance of PAX3 expression protected melanoma cells from the anti-tumor effects of SB216763. These data support a model wherein GSK-3 regulates proliferation and morphology of melanoma through phosphorylation and increased levels of PAX3.
