Discordant regulatory changes in monocrotaline-induced megalocytosis of lung arterial endothelial and alveolar epithelial cells.
Discordant regulatory changes in monocrotaline-induced megalocytosis of lung arterial endothelial and alveolar epithelial cells.
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野百合碱诱导的肺动脉内皮和肺泡上皮细胞巨细胞增多症的不一致调节变化。
DOI：
10.1152/ajplung.00535.2005
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Sehgal,PravinB
中科院分区：
文献类型：
--
作者：
Mukhopadhyay,Somshuvra;Sehgal,PravinB
野百合碱 (MCT) 通过肺动脉内皮 (PAEC)、动脉平滑肌和 II 型肺泡上皮细胞巨细胞增多（内质网和高尔基体增大以及细胞周期停滞的细胞增大）引起大鼠肺动脉高压。在细胞培养中，尽管巨细胞增多与肺内皮细胞和上皮细胞进入有丝分裂的受阻有关，但内皮细胞中的 DNA 合成受到刺激，而上皮细胞中的 DNA 合成受到抑制。这种二分法的分子机制尚不清楚。虽然 MCTP 处理的 PAEC 和肺上皮 (A549) 细胞均显示出“促有丝分裂”转录因子 STAT3 水平和 IL-6 诱导的 PY-STAT3 核库的增加，但这种情况在 A549 中转录失活，但在 PAEC 细胞中则不然。 A549 细胞中 STAT3 转录活性的缺乏与 A549 细胞中 STAT3 共激活因子 CBP/p300 和 SRC1/NcoA 的细胞质隔离相关，但与 PAEC 中无关。两种细胞类型均表现出高尔基体运输受阻、caveolin-1 筏丢失和核 Ire1α 增加，但未折叠蛋白反应 (UPR) 不完全，UPR 诱导的分子伴侣（包括 GRP78/BiP）水平几乎没有变化。两种细胞类型中的细胞周期调节蛋白存在不一致的变化，例如细胞周期蛋白 D1 和 p21 水平同时增加，但 cdc2/cdk1（一种进入有丝分裂所需的激酶）减少。虽然两种细胞类型都显示出细胞质双联蛋白增加，但 DNA 合成起始蛋白 Cdt1 在 PAEC 中主要位于细胞核，但在 A549 细胞中仍然位于细胞质，这与前者刺激 DNA 合成但在后者细胞类型中受到抑制一致。因此，关键调节分子（如 CBP/p300、SRC1/NcoA、Cdt1）亚细胞运输中细胞类型特异性改变的差异可能解释了 MCTP 对内皮细胞和上皮细胞 DNA 合成的影响的二分性。
Monocrotaline (MCT) causes pulmonary hypertension in the rat by a mechanism characterized by megalocytosis (enlarged cells with enlarged endoplasmic reticulum and Golgi and a cell cycle arrest) of pulmonary arterial endothelial (PAEC), arterial smooth muscle, and type II alveolar epithelial cells. In cell culture, although megalocytosis is associated with a block in entry into mitosis in both lung endothelial and epithelial cells, DNA synthesis is stimulated in endothelial but inhibited in epithelial cells. The molecular mechanism(s) for this dichotomy are unclear. While MCTP-treated PAEC and lung epithelial (A549) cells both showed an increase in the “promitogenic” transcription factor STAT3 levels and in the IL-6-induced nuclear pool of PY-STAT3, this was transcriptionally inactive in A549 but not in PAEC cells. This lack of transcriptional activity of STAT3 in A549 cells correlated with the cytoplasmic sequestration of the STAT3 coactivators CBP/p300 and SRC1/NcoA in A549 cells but not in PAEC. Both cell types displayed a Golgi trafficking block, loss of caveolin-1 rafts, and increased nuclear Ire1α, but an incomplete unfolded protein response (UPR) with little change in levels of UPR-induced chaperones including GRP78/BiP. There were discordant alterations in cell cycle regulatory proteins in the two cell types such as increase in levels of both cyclin D1 and p21 simultaneously, but with a decrease in cdc2/cdk1, a kinase required for entry into mitosis. While both cell types showed increased cytoplasmic geminin, the DNA synthesis-initiating protein Cdt1 was predominantly nuclear in PAEC but remained cytoplasmic in A549 cells, consistent with the stimulation of DNA synthesis in the former but an inhibition in the latter cell type. Thus differences in cell type-specific alterations in subcellular trafficking of critical regulatory molecules (such as CBP/p300, SRC1/NcoA, Cdt1) likely account for the dichotomy of the effects of MCTP on DNA synthesis in endothelial and epithelial cells.
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DOI：
10.1002/path.1700400208
发表时间：
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期刊：
The Journal of Pathology and Bacteriology
影响因子：
--
作者：
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作者：
P. Sehgal;J. Darnell;I. Tamm
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