P38SAPK2 phosphorylates cyclin D3 at Thr-283 and targets it for proteasomal degradation.
Cyclin D3 plays a critical role in maturation of precursor T cells and their levels are tightly regulated during this process. Alteration of cyclin D3 levels has been proposed to be important in the development of different human cancers, including malignancies of the lymphoid system. Thus, we have analysed the mechanisms involved in the regulation of cyclin D3 levels. Our results indicate that cyclin D3 is degraded via proteasome and that Thr-283 is essential for its degradation. Wild-type cyclin D3 but not the Thr-283A mutant accumulated ubiquitylated forms after treatment with proteasome inhibitors. We also observed that different type of stresses promote the Thr-283-dependent in vivo degradation of cyclin D3. The analysis of the kinases involved in Thr-283 phosphorylation indicates that all the members of the p38SAPK family of serine-threonine kinases are able to phosphorylate cyclin D3 at this specific site. Moreover, we found that the overexpression of p38alphaSAPK2 induce the decrease of cyclin D3 in vivo. These results indicate that p38SAPK might be involved in the regulation of cyclin D3 levels and suggest that this mechanism is involved in the maturation of precursor T-cells. Alterations of this mechanism might be important for oncogenesis.
Departament de Biologia Cel lular i Anatomia Patològica, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Casanova 143, 08036, Spain.
Oriol
O
Casanovas
Montserrat
M
Jaumot
Ana-Belén
AB
Paules
Neus
N
Agell
Oriol
O
Bachs
D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D056743:Cyclin D3; D016213:Cyclins / Q000737:chemistry / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D017931:DNA Primers; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013912:Threonine / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
C534696:CCND3 protein, human; D056743:Cyclin D3; D016213:Cyclins; D017931:DNA Primers; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D025801:Ubiquitin; D013912:Threonine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex