Osmotic stress regulates the stability of cyclin D1 in a p38SAPK2-dependent manner.
We report here that different cell stresses regulate the stability of cyclin D1 protein. Exposition of Granta 519 cells to osmotic shock, oxidative stress, and arsenite induced the post-transcriptional down-regulation of cyclin D1. In the case of osmotic shock, this effect was completely reversed by the addition of p38(SAPK2)-specific inhibitors (SB203580 or SB220025), indicating that this effect is dependent on p38(SAPK2) activity. Moreover, the use of proteasome inhibitors prevented this down-regulation. Thus, osmotic shock induces proteasomal degradation of cyclin D1 protein by a p38(SAPK2)-dependent pathway. The effect of p38(SAPK2) on cyclin D1 stability might be mediated by direct phosphorylation at specific sites. We found that p38(SAPK2) phosphorylates cyclin D1 in vitro at Thr(286) and that this phosphorylation triggers the ubiquitination of cyclin D1. These results link for the first time a stress-induced MAP kinase pathway to cyclin D1 protein stability, and they will help to understand the molecular mechanisms by which stress transduction pathways regulate the cell cycle machinery and take control over cell proliferation.
Casanovas
O
O
Departament de Biologia Cellular i Anatomia Patològica, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi Sunyer, University of Barcelona, 08036 Barcelona, Spain.
Miró
F
F
Estanyol
J M
JM
Itarte
E
E
Agell
N
N
Bachs
O
O
D018053:Arsenites / Q000494:pharmacology; D015153:Blotting, Western; D002122:Calcium Chloride / Q000494:pharmacology; D002455:Cell Division; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism*; D003546:Cysteine Endopeptidases; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D020935:MAP Kinase Signaling System; D015636:Magnesium Chloride / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009995:Osmosis; D018384:Oxidative Stress; D010766:Phosphorylation; D017354:Point Mutation; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012965:Sodium Chloride / Q000494:pharmacology; D013912:Threonine / Q000737:chemistry; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D018053:Arsenites; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009097:Multienzyme Complexes; D011725:Pyridines; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; C110631:SB 220025; D014452:Ubiquitins; D015636:Magnesium Chloride; D019938:Cyclin D1; D013912:Threonine; D012965:Sodium Chloride; D006861:Hydrogen Peroxide; D005982:Glutathione Transferase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D002122:Calcium Chloride; C015001:arsenite; C093642:SB 203580