TGF-beta-activating kinase-1 inhibits cell cycle and expression of cyclin D1 and A in LLC-PK1 cells.

Abstract:

BACKGROUND:Transforming growth factor-beta (TGF-beta) is known to play an important role in the pathophysiology of renal tubular disease. Researchers have recently identified a novel mitogen-activated protein kinase kinase kinase (MAPKKK), TAK (TGF-beta activated kinase)1, which stimulates the MKK3/6-p38K pathway. The purpose of our study was to investigate the functional role of the TAK1-MKK3/6-p38K pathway and classical MAPK cascades in the progression of the cell cycle in renal tubular cells. METHODS:The constitutive active form and negative form of TAK1 (TAK1dN and TAK1K63W, respectively), and active and negative forms of the p42/44 MAPK-activator, MKK1 (S222E and S222A, respectively) were transfected to LLC-PK1 cells. Western blot analyses and promoter-luciferase assay of cyclins D1, D2, D3, E, and A were performed, and cell cycle progression was analyzed by FACS scan. RESULTS:TAK1dN stimulated MKK6 and p38K activity and inhibited the percentage of the S and G2/M phases. TAK1K63 W inhibited TGF-beta-stimulated MKK6 and p38K activity. Cyclin D1 and cyclin A protein levels and promoter activities were negatively regulated by TAK1dN. In contrast, overexpression of the active form of p42/44 MAPK-activator, MKK1, increased cyclin D1 and A promoter activity and protein levels. CONCLUSION:The growth-inhibitory effects of TGF-beta are at least partially mediated by the TAK1-MKK6-p38K pathway. Cyclin D1 and A promoter activity and cell cycle progression in renal tubular cells are negatively regulated by the TAK1-MKK6-p38K pathway and positively regulated by the MKK1-p42/44MAPK pathway.

journal_name

Kidney Int

journal_title

Kidney international

authors

Terada Y,Nakashima O,Inoshita S,Kuwahara M,Sasaki S,Marumo F

doi

10.1046/j.1523-1755.1999.00665.x

subject

Has Abstract

pub_date

1999-10-01 00:00:00

pages

1378-90

issue

4

eissn

0085-2538

issn

1523-1755

pii

S0085-2538(15)46447-6

journal_volume

56

pub_type

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