耶魯大學(xué)研究人員發(fā)現(xiàn)巨核細(xì)胞(megakaryocyte)---一種產(chǎn)生愈合傷口的血小板的巨大細(xì)胞---如何能夠生長至其他血細(xì)胞的10至15倍大。相關(guān)研究結(jié)果將于2012年3月13日發(fā)表在《細(xì)胞》子刊Developmental Cell期刊上,，有助于人們理解這種過程發(fā)生故障如何可能導(dǎo)致一種類型白血病,，即巨核細(xì)胞白血病(megakaryoblastic leukemia)。
“這些巨核細(xì)胞不能生長可能是導(dǎo)致巨核細(xì)胞白血病形成的初始觸發(fā)器”,，論文通訊作者,、耶魯大學(xué)癌癥中心研究員、耶魯大學(xué)干細(xì)胞中心副主任與實(shí)驗(yàn)室醫(yī)學(xué),、細(xì)胞生物學(xué)和病理學(xué)教授Diane Krause說,。
巨核細(xì)胞生長如此大是因?yàn)榧?xì)胞內(nèi)DNA復(fù)制很多次，但是沒有發(fā)生細(xì)胞分裂,，這一過程被稱作核內(nèi)有絲分裂(endomitosis),。一個(gè)成巨核細(xì)胞在它最終變成生物“超新星(supernova)”之前能夠容納120多套細(xì)胞核DNA，而一旦變成之后,，它就經(jīng)歷深刻變化而分裂成正常血液凝固所必需的上千個(gè)血小板,。
耶魯大學(xué)博士后研究助理Yuan Gao領(lǐng)導(dǎo)的一個(gè)研究小組發(fā)現(xiàn)兩種被稱作鳥苷酸交換因子(guanine exchange factor, GEF-H1)的蛋白能夠抑制核內(nèi)有絲分裂。他們發(fā)現(xiàn)若沒有GEF-H1,，細(xì)胞核DNA不能夠從2個(gè)細(xì)胞內(nèi)核變成4個(gè),。隨后，除非另一個(gè)因子ECT2表達(dá)水平下降,，細(xì)胞內(nèi)細(xì)胞核DNA分裂不可能發(fā)生,。
研究人員發(fā)現(xiàn)一個(gè)與惡性白血病相關(guān)的基因MKL1似乎也是促進(jìn)正常巨核細(xì)胞成熟所必需的，他們對此感到吃驚,。Krause實(shí)驗(yàn)室如今正在研究MKL1基因發(fā)生突變是否可以維持高水平GEF-H1從而使得巨核細(xì)胞不可能經(jīng)歷核內(nèi)有絲分裂,，從而為白血病產(chǎn)生作好鋪墊。
“功能性血小板是正常血液凝固所必需的,，而這些研究發(fā)現(xiàn)揭示功能性血小板形成的另一個(gè)重要性步驟,。不過它們也提供關(guān)于是什么可能發(fā)生偏差而導(dǎo)致正常巨核細(xì)胞轉(zhuǎn)變成惡性白血病細(xì)胞的線索。” (生物谷：towersimper編譯)
doi:10.1016/j.devcel.2011.12.019
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Role of RhoA-Specific Guanine Exchange Factors in Regulation of Endomitosis in Megakaryocytes
Yuan Gao, Elenoe Smith, Elmer Ker, Phil Campbell, Ee-chun Cheng, Siying Zou, Sharon Lin, Lin Wang, Stephanie Halene, Diane S. Krause
Polyploidization can precede the development of aneuploidy in cancer. Polyploidization in megakaryocytes (Mks), in contrast, is a highly controlled developmental process critical for efficient platelet production via unknown mechanisms. Using primary cells, we demonstrate that the guanine exchange factors GEF-H1 and ECT2, which are often overexpressed in cancer and are essential for RhoA activation during cytokinesis, must be downregulated for Mk polyploidization. The first (2N–4N) endomitotic cycle requires GEF-H1 downregulation, whereas subsequent cycles (>4N) require ECT2 downregulation. Exogenous expression of both GEF-H1 and ECT2 prevents endomitosis, resulting in proliferation of 2N Mks. Furthermore, we have shown that the mechanism by which polyploidization is prevented in Mks lacking Mkl1, which is mutated in megakaryocytic leukemia, is via elevated GEF-H1 expression; shRNA-mediated GEF-H1 knockdown alone rescues this ploidy defect. These mechanistic insights enhance our understanding of normal versus malignant megakaryocytopoiesis, as well as aberrant mitosis in aneuploid cancers.
doi:10.1016/j.devcel.2012.02.010
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GEFs on the RhoAd to a Colossal Nucleus
Ramesh A. Shivdasani
Cytokinesis in normal cell division requires RhoA-regulated actomyosin contraction of the cleavage furrow; this process is aborted in megakaryocyte endomitosis, leading to polyploidy. In this issue of Developmental Cell, Gao et al., 2012 trace the basis of endomitosis to sequential downregulation of guanine nucleotide exchange factors GEF-H1 and ECT2.
