Document Detail

Discordant regulatory changes in monocrotaline-induced megalocytosis of lung arterial endothelial and alveolar epithelial cells.
MedLine Citation:
PMID:  16414977     Owner:  NLM     Status:  MEDLINE    
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 Ire1alpha, 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.
Somshuvra Mukhopadhyay; Pravin B Sehgal
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-01-13
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  290     ISSN:  1040-0605     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2006 Jun 
Date Detail:
Created Date:  2006-05-10     Completed Date:  2006-08-11     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L1216-26     Citation Subset:  IM    
Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA.
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MeSH Terms
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / analogs & derivatives,  pharmacology
Cell Division / drug effects
Cell Line
Cell Separation
Interleukin-6 / pharmacology
Monocrotaline / pharmacology*
Pulmonary Alveoli / cytology,  drug effects,  physiology
Pulmonary Artery / drug effects,  physiology*
Respiratory Mucosa / cytology*,  drug effects,  physiology*
STAT3 Transcription Factor / genetics
Transcription, Genetic / drug effects
Grant Support
Reg. No./Substance:
0/Interleukin-6; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 106351-84-2/1-methyl-4-cyclohexyl-1,2,3,6-tetrahydropyridine; 28289-54-5/1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 315-22-0/Monocrotaline

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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