title: Degradation of c-Fos by the 26S proteasome is accelerated by c-Jun and multiple protein kinases.
abstract: c-Fos is associated with c-Jun to increase the transcription of a number of target genes and is a nuclear proto-oncoprotein with a very short half-life. This instability of c-Fos may be important in regulation of the normal cell cycle. Here we report a mechanism for degradation of c-Fos. Coexpression of c-Fos and c-Jun in HeLa cells caused marked increase in the instability of c-Fos, whereas v-Fos, the retroviral counterpart of c-Fos, was stable irrespective of the coexpression of c-Jun. Interestingly, deletion of the C-terminal PEST region of c-Fos, which is altered in v-Fos by a frameshift mutation, greatly enhanced its stability, with loss of the effect of c-Jun on its stability. c-Fos synthesized in vitro was degraded by the 26S proteasome in a ubiquitin-dependent fashion. Simple association with c-Jun had no effect on the degradation of c-Fos, but the additions of three protein kinases, mitogen-activated protein kinase, casein kinase II, and CDC2 kinase, resulted in marked acceleration of its degradation by the proteasome-ubiquitin system, though only in the presence of c-Jun. In contrast, v-Fos and c-Fos with a truncated PEST motif were not degraded, suggesting that they escaped from down-regulation by breakdown. These findings indicate a new oncogenic pathway induced by acquisition of intracellular stability of a cell cycle modulatory factor.
authors.affiliation: Institute for Enzyme Research, University of Tokushima, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Tsurumi
authors.forename: N
authors.initials: N
authors.lastname: Ishida
authors.forename: T
authors.initials: T
authors.lastname: Tamura
authors.forename: A
authors.initials: A
authors.lastname: Kakizuka
authors.forename: E
authors.initials: E
authors.lastname: Nishida
authors.forename: E
authors.initials: E
authors.lastname: Okumura
authors.forename: T
authors.initials: T
authors.lastname: Kishimoto
authors.forename: M
authors.initials: M
authors.lastname: Inagaki
authors.forename: K
authors.initials: K
authors.lastname: Okazaki
authors.forename: N
authors.initials: N
authors.lastname: Sagata
mesh_terms: D000595:Amino Acid Sequence; D016368:Frameshift Mutation; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D014452:Ubiquitins / Q000502:physiology
chemical_list: D016761:Oncogene Proteins v-fos; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014452:Ubiquitins; D017346:Protein Serine-Threonine Kinases; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease