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Cellular mechanisms in monocrotaline‐induced megalocytosis in pulmonary hypertension
Author(s) -
Mukhopadhyay Somshuvra,
Sehgal Pravin B
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a402-d
Subject(s) - microbiology and biotechnology , unfolded protein response , cyclin d1 , a549 cell , cyclin a , biology , cyclin , stat3 , cell cycle , cyclin d , cancer research , chemistry , signal transduction , cell , endoplasmic reticulum , biochemistry
Pulmonary hypertension (PH) is a progressive disease whose initiating event far precedes clinical symptoms. In the monocrotaline pyrrole (MCTP) model of PH we have previously shown that the development of PH was associated with (a) hyperactivation of IL‐6/STAT3 signaling, (b) disruption of cav‐1/raft scaffolding, (c) a block in trafficking from/through the Golgi (“Golgi blockade hypothesis”), and (d) an unfolded protein response (UPR). We have now delineated the UPR signaling pathways affected by MCTP and changes in cell‐cycle regulators. While in lung epithelial cells (A549) MCTP caused a nuclear translocation of IRE‐1α, indicative of induction of the UPR, there was no change in the levels of chaperone proteins. ATF‐6 was trapped in a perinuclear compartment and there was an increase in a 200‐kDa complex cross‐reactive with a XBP‐1 antibody. MCTP treatment of A549 and lung endothelial (BPAEC) cells caused a 5‐ to 8‐fold increase in total STAT3 levels with an increase in IL‐6‐induced PY‐STAT3 signaling. There was an associated increase in the STAT3‐inducible gene products cyclin D1 and p21, as well as of cyclin D3. A549 cells however, had decreased levels of cyclin B1 and cdc2 but increased nuclear Cdt1, indicative of slowed transit through the cell cycle. 35 S‐methionine pulse‐chase experiments confirmed that the increased levels of STAT3, cyclin D1, and p21 in MCTP‐treated A549 cells were due to increased synthesis per se . These data show that (a) MCTP‐induced megalocytosis was accompanied by a modified UPR (content of chaperone proteins did not increase), and (b) highlight potential STAT3‐mediated downstream alterations in cell‐cycle regulatory proteins. Supported by NIH HL‐73301.