GLYCOGEN SYNTHASE KINASE-3BETA REGULATES CYCLIN D1 PROTEOLYSIS AND SUBCELLULAR LOCALIZATION

摘要: A family of cyclin-dependent kinases (CDKs) cooperatively regulates mammalian cell cycle progression (for review, see Sherr 1993). During G1 phase, D-type cyclins (D1, D2, and D3) are synthesized assemble with either CDK4 or CDK6 in response to growth factor stimulation, thereby generating active holoenzymes that help inactivate the growth-suppressive function retinoblastoma protein (Rb) through its phosphorylation Weinberg 1995). Cyclin D holoenzyme complexes also titrate CDK inhibitors, such as p27Kip1 p21Cip1, facilitating activation cyclin E-CDK2 subsequent entry into DNA synthetic phase Roberts 1995). Ras-mediated pathways important for D1 induction assembly CDKs. Overexpression activated oncogenic Ras alleles, but not wild-type Ras, initiates synthesis independently stimulation (Feramisco et al. 1984). Conversely, microinjection antibodies introduction certain dominant-negative alleles can block S-phase induced by mitogens (Mulcahy 1985; Mittnacht 1997; Peeper 1997). Both expression require sequential activities Raf1, mitogen-activated kinase-kinases (MEK1 MEK2), sustained extracellular signal-regulated (ERKs; Albanese 1995; Lavoie 1996; Winston Aktas Kerkhoff Rapp Weber Cheng 1998). In turn, degradation is mediated phosphorylation-triggered, ubiquitin-dependent proteolysis (Diehl Polyubiquitination substrates involves action three distinct enzymes termed E1, E2 (UBC; ubiquitin-conjugating enzyme), E3 (ubiquitin ligase; Ciechanover 1994; King 1996). Specificity substrate recognition dependent on several factors including selectivity (King Skowyra Renny-Feldman 1997), motifs within target proteins themselves (Glotzer 1991), and, some cases, a requirement specific residues (Deshaies Clurman Lanker Won Ubiquitin-dependent requires threonine residue (Thr-286) located near carboxyl terminus, this D-dependent Because kinase phosphorylates has yet been identified, it remains unclear whether proteolysis, like assembly, subject mitogen regulation. The subcellular distribution likely be regulated cycle-dependent events. accumulates nuclei cells during once replication begins, disappears from nucleus (Baldin 1993), despite fact level does decrease markedly S (Matsushime 1991). The mechanisms regulate periodic redistribution division have defined. We now demonstrate glycogen synthase kinase-3β (GSK-3β) catalyzes Thr-286, regulating turnover mitogenic signals. In GSK-3β-mediated redirects cytoplasm. Our results support model which Thr-286 GSK-3β links processes governing localization proteasomal degradation.