mel-18 negatively regulates cell cycle progression upon B cell antigen receptor stimulation through a cascade leading to c-myc/cdc25.
mel-18 is a mammalian Polycomb group gene encoding a transcriptional repressor with tumor suppressive activity. Overexpression of mel-18 in mice results in cell cycle arrest of B cells upon B cell receptor stimulation with downregulation of c-myc. This phenotype is rescued in mel-18/c-myc double-transgenic mice, suggesting that c-myc locates downstream of mel-18. In mel-18 transgenic mice, the downregulation of cyclins D2 and E; CDK4, -6, and -7; and CDC25A causes the impairment in the activities of cyclin-dependent kinases, resulting in hypophosphorylation of the retinoblastoma protein. In contrast, the upregulation of c-Myc, CDC25, and CDC2/CDK2 kinase activities results in the augmentation of B cell proliferation in mel-18-deficient mice. We therefore propose that mel-18 negatively regulates the cell cycle through a c-myc/cdc25 cascade.
Tetsu
O
O
Department of Molecular Immunology, Graduate School of Medicine Chiba University, Japan.
Ishihara
H
H
Kanno
R
R
Kamiyasu
M
M
Inoue
H
H
Tokuhisa
T
T
Taniguchi
M
M
Kanno
M
M
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015536:Down-Regulation; D016193:G1 Phase; D015870:Gene Expression; D016762:Genes, fos; D016259:Genes, myc; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010749:Phosphoprotein Phosphatases / Q000235:genetics; D063150:Polycomb Repressive Complex 1; D011401:Promoter Regions, Genetic; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D012097:Repressor Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D020687:cdc25 Phosphatases
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C489348:PCGF2 protein, human; C066476:Pcgf6 protein, mouse; D011947:Receptors, Antigen, B-Cell; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D063150:Polycomb Repressive Complex 1; D010749:Phosphoprotein Phosphatases; D020687:cdc25 Phosphatases