Induction of homologue of Slimb ubiquitin ligase receptor by mitogen signaling.
Homologue of Slimb (HOS) is the substrate-recognizing component of the SCF(HOS)-Roc1 E3 ubiquitin protein ligase. This ligase mediates ubiquitination of the inhibitor of NF-kappaB transcription factor (IkappaB). We have found that HOS is highly expressed in a number of human cancer cell lines. The rates of the HOS gene transcription as well as HOS mRNA and protein levels were up-regulated in cells treated with mitogens or transfected with the inducers of mitogen-activated protein kinase pathway. Conversely, mitogen withdrawal strikingly reduced HOS levels during differentiation of mouse myoblasts. Activators of mitogen-activated protein kinase accelerated IkappaBalpha degradation and increased NF-kappaB transcriptional activity. Inhibition of HOS function via expression of dominant negative HOS (HOS(DeltaF)) initiated mouse myoblast differentiation and prevented Ras-mediated acceleration of IkappaBalpha degradation as well as NF-kappaB trans-activation and transformation of NIH3T3 cells. These data link the induction of HOS in proliferating cells with mitogen-signaling-dependent inhibition of cell differentiation and promotion of cell transformation.
Spiegelman
Vladimir S
VS
AMC Cancer Research Center, Lakewood, Colorado 80214, USA.
Tang
Weigang
W
Chan
Andrew M
AM
Igarashi
Makoto
M
Aaronson
Stuart A
SA
Sassoon
David A
DA
Katoh
Masaru
M
Slaga
Thomas J
TJ
Fuchs
Serge Y
SY
D016475:3T3 Cells; D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D015151:Immunoblotting; D008025:Ligases / Q000378:metabolism*; D051379:Mice; D008934:Mitogens / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011233:Precipitin Tests; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism*
D008934:Mitogens; D016328:NF-kappa B; D025801:Ubiquitin; D009955:Ornithine Decarboxylase; D008025:Ligases