p21waf1/cip1 is down-regulated in conjunction with up-regulation of c-Fos in the lymphocytes of rheumatoid arthritis patients.
Features characteristic to rheumatoid arthritis (RA) including synovial overgrowth and joint destruction are experimentally produced by augmenting c-fos gene expression. We show that cyclin dependent kinase inhibitor p21waf1/cip1, that inhibits cell proliferation, is down-regulated in conjunction with up-regulation of c-fos in the lymphocytes of patients with RA. As to the mechanism of down-regulation of p21waf1/cip1 gene expression, transfection studies in U937 cells showed that c-fos down-regulated phosphorylation and dimerization of signal transducers and activators of transcription (STAT) 1, thereby inhibiting interferon -induced transactivation of p21waf1/cip1. Phosphorylation of STAT1 was indeed decreased in the lymphocytes of patients with RA. Thus, under overexpression of c-fos gene, c-Fos inactivates STAT1 to down-regulate p21waf1/cip1 gene expression in the lymphocytes of patients with RA, and in this way may enhance proliferation of lymphocytes.
Hikasa
Mari
M
Department of Rheumatology, Faculty of Health Science, Kobe University School of Medicine, 654-0142, Kobe, Japan.
Yamamoto
Eri
E
Kawasaki
Hiroki
H
Komai
Koichiro
K
Shiozawa
Kazuko
K
Hashiramoto
Akira
A
Miura
Yasushi
Y
Shiozawa
Shunichi
S
D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism*; D008954:Models, Biological; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism* / Q000502:physiology; D050794:STAT1 Transcription Factor; D012926:Social Control, Formal; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D020298:U937 Cells; D015854:Up-Regulation
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D016760:Proto-Oncogene Proteins c-fos; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma