Caveolin-1-mediated post-transcriptional regulation of inducible nitric oxide synthase in human colon carcinoma cells.
Reactive oxygen species are now widely recognized as important players contributing both to cell homeostasis and the development of disease. In this respect nitric oxide (NO) is no exception. The discussion here will center on regulation of the inducible form of nitric oxide synthase (iNOS) for two reasons. First, only iNOS produces micromolar NO concentrations, amounts that are high by comparison with the picomolar to nanomolar concentrations resulting from Ca2(+)-controlled NO production by endothelial eNOS or neuronal nNOS. Second, iNOS is not constitutively expressed in cells and regulation of this isoenzyme, in contrast to endothelial eNOS or neuronal nNOS, is widely considered to occur at the transcriptional level only. In particular, we were interested in the possibility that caveolin-1, a protein that functions as a tumor suppressor in colon carcinoma cells (Bender et al., 2002; this issue), might regulate iNOS activity. Our results provide evidence for the existence of a post-transcriptional mechanism controlling iNOS protein levels that involves caveolin-1-dependent sequestration of iNOS within a detergent-insoluble compartment. Interestingly, despite the high degree of conservation of the caveolin-1 scaffolding domain binding motif within all NOS enzymes, the interaction detected between caveolin-1 and iNOS in vitro is crucially dependent on presence of a caveolin-1 sequence element immediately adjacent to the scaffolding domain. A model is presented summarizing the salient aspects of these results. These observations are important in the context of tumor biology, since down-regulation of caveolin-1 is predicted to promote uncontrolled iNOS activity, genotoxic damage and thereby facilitate tumor development in humans.
Felley-Bosco
Emanuela
E
Institute of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
Bender
Florent
F
Quest
Andrew F G
AF
D051242:Caveolin 1; D022461:Caveolins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D003110:Colonic Neoplasms / Q000378:metabolism; D003546:Cysteine Endopeptidases; D006801:Humans; D009097:Multienzyme Complexes; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D017382:Reactive Oxygen Species; D020539:Sequence Analysis, Protein; D015398:Signal Transduction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000378:metabolism
C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex