Abstract
P311 is a mouse cDNA originally identified for its high expression in late-stage embryonic brain and adult cerebellum, hippocampus, and olfactory bulb. The protein product of P311, however, had not been identified previously, and its function remains unknown. We report here that P311 expression is regulated at multiple levels by pathways that control cellular transformation. P311 mRNA expression was decreased sharply in both neural and smooth muscle cells when the cells were transformed by coexpression of the oncogenic tyrosine kinase receptor Met and its ligand hepatocyte growth factor/scatter factor. The P311 mRNA was found to encode an 8-kDa polypeptide that was subject to rapid degradation by the lactacystin-sensitive ubiquitin/proteasome system and an unidentified metalloprotease, resulting in a protein half-life of about 5 min. These data suggest that P311 expression is dramatically decreased by several pathways that regulate cellular growth.
Highlights
Our recent efforts have been aimed at understanding the ability of Met to initiate primary tumor growth and metastasis at the molecular level, and toward that end, we have identified several genes whose expression is regulated by Met action
Because SK-LMS cells are transformed smooth muscle cells we examined P311 expression in normal human intestinal smooth muscle cells, in which we found extremely high P311 mRNA levels (Fig. 1), suggesting a progressive decrease in P311 expression in increasingly more transformed smooth muscle cells
We have shown that P311 expression is tightly regulated at several levels by mechanisms that control cellular growth and transformation
Summary
Vol 275, No 6, Issue of February 11, pp. 4215–4219, 2000 Printed in U.S.A. Regulation of P311 Expression by Met-Hepatocyte Growth Factor/ Scatter Factor and the Ubiquitin/Proteasome System*. The P311 mRNA was found to encode an 8-kDa polypeptide that was subject to rapid degradation by the lactacystin-sensitive ubiquitin/proteasome system and an unidentified metalloprotease, resulting in a protein half-life of about 5 min These data suggest that P311 expression is dramatically decreased by several pathways that regulate cellular growth. We found a new Met-HGF/SFregulated mRNA, P311 [12], that was down-regulated by Met signaling in several types of transformed cells We found that this mRNA encoded a relatively small intracellular protein that was targeted for degradation by multiple proteolytic pathways including the ubiquitin/proteasome, resulting in an extremely short protein half-life. Expression of the P311 gene was under tight regulation by several mechanisms that regulate cellular growth
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