Proteasomal activity modulates TGF-ss signaling in a gene-specific manner.
Transforming growth factor-beta (TGF-beta) signaling relies on Smad-signaling pathway controlled in part by the proteasome. Here we demonstrate that inhibition of the proteasome function in mink epithelial cells accumulates both positive and negative modulators of TGF-beta signaling, phospho-Smad2 and SnoN. Inhibition of the proteasome led to abrogation of TGF-beta target gene regulation in a gene-specific manner. While regulation of p15Ink4b and myc by TGF-beta are lost, PAI-1 induction, previously shown to occur in a Smad3-dependent manner, was not affected by treatment of the cells with the proteasomal inhibitor MG132. The results suggest that proteasomal activity is required for TGF-beta signaling in a gene-specific manner.
Zhang
Fan
F
Haartman Institute, Department of Virology and Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital Laboratory Diagnostics, P.O. Box 63, FIN-00014, Helsinki, Finland.
Mönkkönen
Mia
M
Roth
Stina
S
Laiho
Marikki
M
D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D050762:Cyclin-Dependent Kinase Inhibitor p15; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D007976:Leupeptins; D008907:Mink; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D017395:Plasminogen Activator Inhibitor 1; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde