Up-regulation of Cks1 and Skp2 with TNFα/NF-κB signaling in chronic progressive nephropathy.
The cyclin-dependent kinase (CDK) inhibitor p27 level is associated with progression of renal damage. We previously reported that mRNA of Skp2, a component of Skp/Cullin/F-box (SCF)-ubiquitin ligase which targets to p27, was increased in unilateral ureteral obstructive kidneys in mice and that the nephritis was attenuated in Skp2-deficient mice. However, the details have not been fully clarified. Here, we found that not only Skp2 but also cdc kinase subunit 1 (Cks1), an essential cofactor for the SCF-Skp2 ubiquitin ligase in targeting p27, was increased in another chronic progressive model, anti-thymocyte serum (ATS) rat nephropathy. After induction of ATS nephropathy, Skp2(+) /Cks1(+) /Ki67(+) tubular epithelial cell numbers increased, and p27(+) tubular epithelial cells decreased transiently. Moreover, we found that TNFα was involved in expression of both Skp2 and Cks1 in NRK cell line as well as the in ATS nephropathy. Nuclear accumulations of NF-κB subunits RelB and p52 were increased in the tubular epithelial cells of the nephritic kidney. Both Skp2 and Cks1 were colocalized with RelB in these cells. These data suggest that both Skp2 and Cks1 are up-regulated by the TNFα-RelB/p52 pathway in the early stages of renal damage and are collaboratively involved in down-regulation of p27 in proliferative tubular dilation and the progression of chronic nephropathy.
Department of Biochemistry 1, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.
Sayuri
S
Suzuki
Hirotaka
H
Fukasawa
Taro
T
Misaki
Akashi
A
Togawa
Naro
N
Ohashi
Kyoko
K
Kitagawa
Yojiro
Y
Kotake
Hiroyuki
H
Niida
Akira
A
Hishida
Tatsuo
T
Yamamoto
Masatoshi
M
Kitagawa
D000818:Animals; D000961:Antilymphocyte Serum / Q000737:chemistry; D042846:CDC2-CDC28 Kinases / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D002908:Chronic Disease; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009393:Nephritis / Q000139:chemically induced / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000961:Antilymphocyte Serum; C570159:Cks1l protein, rat; D019394:Ki-67 Antigen; D016328:NF-kappa B; D044786:S-Phase Kinase-Associated Proteins; D014409:Tumor Necrosis Factor-alpha; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044843:SKP Cullin F-Box Protein Ligases; D042846:CDC2-CDC28 Kinases