Author:
Mukhopadhyay Somshuvra,Sehgal Pravin B.
Abstract
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.
Publisher
American Physiological Society
Subject
Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology
Reference57 articles.
1. The ultrastructure of the enlarged hepatocytes induced in rats with a single oral dose of retrorsine, a pyrrolizidine (Senecio) alkaloid
2. Armstrong SJand Zuckerman AJ.The effects of lasiocarpine, retrorsine and retronecine pyrrole on human embryo lung and liver cells in culture.Br J Exp Pathol53: 138–144, 1972.
3. PERK mediates cell-cycle exit during the mammalian unfolded protein response
4. Buettner R, Kortylewski M, Pardoll D, Yu H, and Jove R.STAT proteins as molecular targets for cancer therapy. In:Signal Transducers and Activators of Transcription (STATs): Activation and Biology, edited by Sehgal PB, Levy DE, and Hirano T. Dordrecht, The Netherlands: Kluwer Academic Publishers, 2003, p. 645–661.
5. THE HISTOLOGICAL EVIDENCE OP LIVER DAMAGE FROM PYRROLIZIDINE ALKALOIDS:.
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