Nephrology Dialysis Transplantation, Vol 14, Issue 90001 45-47, Copyright © 1999 by Oxford University Press
Y Terada, O Nakashima, S Inoshita, M Kuwahara, S Sasaki and F Marumo
Recent studies have revealed that mitogen-activated protein kinase (MAPK)
consists of at least three subfamilies, namely classical MAPK (also known
as ERK), stress-activated protein kinase/c-Jun N-terminal kinase (JNK) and
p38 kinase. TGF-{beta}-activating kinase (TAK)-1 is a novel MAPKKK which
is reported to stimulate p38K and/or the JNK pathway. To elucidate the
functional roles of the TAK1 pathway, we transfected its constitutive
active form (TAK1dN) and negative form (TAK1K63W) into LLC-PK1 cells. TAKdN
inhibited [3H]thymidine uptake and reduced the
percentages of S and G2/M phases. TAK1K63W ameliorated the inhibitory
effects of TGF-{beta} on [3H]thymidine uptake and
increased the percentages of S and G2/M phases. Western blot analysis
demonstrates that the level of cyclin D1 protein was regulated negatively
by overexpression of TAK1dN. Moreover, overexpression of TAK1dN inhibited
cyclin D1 promoter activity. In contrast, constitutive active MKK1, the
classical p42/44 MAPK activator, increased cyclin D1 promoter activity and
level of protein. Over-expression of the active form of MKK1 increased
[3H]thymidine uptake, while the inactive form
decreased the uptake. In conclusion, cyclin D1 promoter activity and cell
cycle progression are regulated negatively by the TAK1 pathway and
positively by the classical MAPK pathway.Keywords:
cell cycle; cyclin D1; kidney; proliferation; TGF-{beta}
ORIGINAL ARTICLES
Mitogen-activated protein kinase cascade and transcription factors: the opposite role of MKK3/6-p38K and MKK1-MAPK
Second Department of Internal Medicine, Tokyo Medical and Dental University, 5-45, Yushima 1-chome, Bunkyo-ku, Tokyo 113-8519, Japan; Corresponding author
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