2012年9月8日 訊 /生物谷BIOON/ --來自美國加州大學(xué)洛杉磯分校的干細(xì)胞研究人員證實(shí)兩種常見性的腫瘤抑制基因TSC和PTEN在調(diào)節(jié)提供果蠅體內(nèi)血液供應(yīng)的干細(xì)胞樣前體細(xì)胞(stem cell-like precursor cell)中發(fā)揮著至關(guān)重要的作用,。論文通信作者Julian A. Martinez-Agosto博士說，研究人員研究了這些前體細(xì)胞利用TOR信號通路來測量營養(yǎng)水平和壓力,。
Martinez-Agosto說,，“我們想知道一種有機(jī)體在它的組織受傷和修復(fù)過程中制造多少細(xì)胞和何時(shí)制造它們。特別地,，我們想知道這些血前體細(xì)胞如何檢測這種變化和何時(shí)是制造更多血細(xì)胞的時(shí)間,。我們發(fā)現(xiàn)這種TOR通路利用這兩種基因來調(diào)節(jié)它的功能，當(dāng)被激活時(shí),，它增加果蠅血液中血前體細(xì)胞的數(shù)量,。”
這項(xiàng)研究于2012年9月5日在線發(fā)表在同行評審的Development期刊上,。論文第一作者M(jìn)ichelle Dragojlovic-Munther發(fā)現(xiàn)TOR活性增加的前體細(xì)胞具有競爭優(yōu)勢，從而允許它們分裂并制造更多的自己,，因此它們能夠制造血液,。Dragojlovic-Munther發(fā)現(xiàn)這些前體細(xì)胞還具有高水平的活性?；钚匝跏前ㄗ杂苫趦?nèi)的離子或非常小的分子,，而且它們能夠傷害細(xì)胞和讓人容易衰老和患上心臟病。但是在這項(xiàng)研究中,，活性氧是有價(jià)值的,。
Martinez-Agosto說，這些前體細(xì)胞一直在產(chǎn)生活性氧,，而且當(dāng)TOR被激活時(shí),，活性氧水平顯著性地增加。太多的活性氧導(dǎo)致它們比平常時(shí)發(fā)生更加多的分裂,。如果他們利用降低活性氧水平的抗氧化劑處理果蠅,，那么這些細(xì)胞將正常發(fā)育。
這些研究發(fā)現(xiàn)可能是重要的,，這是因?yàn)門OR通路在很多癌癥中被異常地激活,，而且它可能靶向ROS水平，從而可能有助于調(diào)節(jié)這種通路,。
Martinez-Agosto補(bǔ)充道,，特異性靶向的抗氧化劑可能是一小部分血液疾病的潛在治療方法，“這項(xiàng)研究可能告訴我們的就是太多的活性氧導(dǎo)致更多的細(xì)胞發(fā)生分裂,，并且我們可能能夠靶向降低活性氧的療法從而顯著性地改善疾病,。有時(shí)，這種通路過分活躍,，因而我們需要合適的活性氧含量來加以平衡,。這就是不能太少，也不能太多,。我們僅需要的就是剛剛合適,。”
研究人員在研究中陳述道，“這項(xiàng)研究著重強(qiáng)調(diào)了TSC和PTEN在TOR功能上的機(jī)制上差異,，并且證實(shí)一種檢測營養(yǎng)的通路通過調(diào)節(jié)活性氧水平而在協(xié)調(diào)髓系特異性的血前體細(xì)胞的增殖和分化中發(fā)揮著多種作用,，而且當(dāng)這種調(diào)節(jié)被解除時(shí)，它會導(dǎo)致骨髓增生性疾病,。”(生物谷Bioon.com)
doi: 10.1242/dev.074203
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PMID:
Multifaceted roles of PTEN and TSC orchestrate growth and differentiation of Drosophila blood progenitors
Michelle Dragojlovic-Munther and Julian A. Martinez-Agosto
The innate plasticity of hematopoietic progenitors is tightly regulated to supply blood cells during normal hematopoiesis and in response to stress or infection. We demonstrate that in the Drosophila lymph gland (LG) the tumor suppressors TSC and PTEN control blood progenitor proliferation through a common TOR- and 4EBP-dependent pathway. Tsc2 or Pten deficiency in progenitors increases TOR signaling and causes LG overgrowth by increasing the number of actively dividing cells that accumulate high levels of phosphorylated (p) 4EBP during a critical window of growth. These phenotypes are associated with increased reactive oxygen species (ROS) levels in the LG, and scavenging ROS in progenitors is sufficient to rescue overgrowth. Blood progenitor number is also sensitive to starvation and hypoxia in a TOR-dependent manner. Differences between Tsc1/2 and Pten function become apparent at later stages. Loss of Tsc1/2 autonomously increases p4EBP and decreases pAKT levels, expands the number of intermediate progenitors and limits terminal differentiation, except for a late induction of lamellocytes. By contrast, absence of PTEN increases p4EBP and pAKT levels and induces myeloproliferative expansion of plasmatocytes and crystal cells. This increased malignancy is associated with non-autonomous increases in p4EBP levels within peripheral differentiating hemocytes, culminating in their premature release into circulation and demonstrating potential non-autonomous effects of Pten dysfunction on malignancy. This study highlights mechanistic differences between TSC and PTEN on TOR function and demonstrates the multifaceted roles of a nutrient-sensing pathway in orchestrating proliferation and differentiation of myeloid-specific blood progenitors through regulation of ROS levels and the resulting myeloproliferative disorder when dysregulated.
