無(wú)論是在胚胎發(fā)育階段還是成體階段,，神經(jīng)干細(xì)胞的自我增殖都受到內(nèi)因基因表達(dá)水平及外因微環(huán)境的精細(xì)調(diào)控,，這種調(diào)控作用與神經(jīng)系統(tǒng)的正常發(fā)育,、腦功能的維持和修復(fù)都有密切關(guān)系,。
近日,，由中科院上海藥物研究所李佳研究員,、南發(fā)俊研究員和馮林音研究員課題組等協(xié)作進(jìn)行的對(duì)小分子化合物調(diào)控神經(jīng)干細(xì)胞命運(yùn)及其作用機(jī)制研究中,，首次發(fā)現(xiàn)了小分子化合物AICAR對(duì)永生化神經(jīng)干細(xì)胞C17.2及來(lái)源于不同發(fā)展時(shí)期，及不同部位來(lái)源的神經(jīng)干細(xì)胞均有明顯誘導(dǎo)分化為神經(jīng)膠質(zhì)細(xì)胞的作用,，該作用可能并不依賴于其傳統(tǒng)胞內(nèi)靶點(diǎn)AMPK信號(hào)通路,。同時(shí)還發(fā)現(xiàn)AICAR能通過(guò)下調(diào)細(xì)胞內(nèi)cyclin D及磷酸化Rb，從而阻斷神經(jīng)干細(xì)胞分裂周期,，抑制其增殖速度,。基于腺苷激酶抑制劑ITU,、AMPK特異性抑制劑compound C及無(wú)活性突變形式DN-AMPK過(guò)表達(dá)能一定程度的阻斷AICAR的抑制增殖作用等的研究結(jié)果,，表明AICAR的這一抑制增殖作用可能仍然依賴于AMPK 信號(hào)通路的激活。此外研究人員還觀察到低糖作為一種生理性的能量缺乏刺激,，也能激活神經(jīng)干細(xì)胞AMPK 信號(hào)通路,，同時(shí)通過(guò)下調(diào)cyclin D及Rb磷酸化水平引起其周期阻滯于G1/G0期，從而抑制神經(jīng)干細(xì)胞的增殖,，該作用也同樣能一定程度被compound C及DN-AMPK過(guò)表達(dá)所逆轉(zhuǎn),，這也再次提示了AMPK可能在面對(duì)外界能量匱乏環(huán)境下調(diào)控神經(jīng)干細(xì)胞增殖中發(fā)揮重要作用。
以上結(jié)果已在《生物化學(xué)雜志》（J. Biol. Chem.）上發(fā)表,，為能量監(jiān)控器AMPK可能在神經(jīng)干細(xì)胞乃至其他干細(xì)胞適應(yīng)外界環(huán)境的生理過(guò)程中起基礎(chǔ)作用提供重要線索,。（生物谷Bioon.com）
生物谷推薦原始出處：
JBC January 14, 2009, doi: 10.1074/jbc.M806887200
AMP-activated Protein Kinase Is Involved in Neural Stem Cell Growth Suppression and Cell Cycle Arrest by 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside and Glucose Deprivation by Down-regulating Phospho-retinoblastoma Protein and Cyclin D*
Yi Zang, Li-Fang Yu, Fa-Jun Nan, Lin-Yin Feng§ and Jia Li1
The fate of neural stem cells (NSCs), including their proliferation, differentiation, survival, and death, is regulated by multiple intrinsic signals and the extrinsic environment. We had previously reported that 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) directly induces astroglial differentiation of NSCs by activation of the Janus kinase (JAK)/Signal transducer and activator of transcription 3 (STAT3) pathway independently of AMP-activated protein kinase (AMPK). Here, we reported the observation that AICAR inhibited NSC proliferation and its underlying mechanism. Analysis of caspase activity and cell cycle showed that AICAR induced G1/G0 cell cycle arrest in NSCs, associated with decreased levels of poly(ADP-ribose) polymerase, phospho-retinoblastoma protein (Rb), and cyclin D but did not cause apoptosis. Iodotubericidin and Compound C, inhibitors of adenosine kinase and AMPK, respectively, or overexpression of a dominant-negative mutant of AMPK, but not JAK inhibitor, were able to reverse the anti-proliferative effect of AICAR. Glucose deprivation also activated the AMPK pathway, induced G0/G1 arrest, and suppressed the proliferation of NSCs, an effect associated with decreased levels of phospho-Rb and cyclin D protein. Furthermore, Compound C and overexpression of dominant-negative AMPK in C17.2 NSCs could block the glucose deprivation-mediated down-regulation of cyclin D and partially reverse the suppression of proliferation. These results suggest that AICAR and glucose deprivation might induce G1/G0 cell cycle arrest and suppress proliferation of NSCs via phospho-Rb and cyclin D down-regulation. AMPK, but not JAK/STAT3, activation is key for this inhibitory effect and may play an important role in the responses of NSCs to metabolic stresses such as glucose deprivation.
