GENE THERAPY OF GLOMERULONEPHRITIS BY GENE TRANSFER OF CELL CYCLE-RELATED GENES.

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Recent studies have revealed that mitogen-actiated protein kinase(MAPK)consists of at least three subfamilies, namely include classical MAPK(also known as ERK), stress-activated protein kinase/c-Jun N-terminal kinase(JNK), and p38 kinase. TGF-b-activating kinase(TAK)-1 is a novel MAPKKK which is reported to stimulate p38K and/or JNK pathway. To elucidate functional roles of the TAK1 pathway, we transfected its constitutive active form(TAKdN)and negative form(TAKK63W)to LLCPK1 cells. TAKdN inhibited 3H-thymidine uptake, and reduced the percentages of S and G2/M phases. TAKK63W ameliorated inhibition of 3H-thymidine uptake and the percentages of S and G2/M phases by TGF-b. Western blot analysis demonstrates that the cyclin D1 protein level was negatively regulated by overexpression of TAKdN.Moreover, overexpression of TAKdN inhibited cyclin D1 promoter activity. In contract, constitutive active MKK1, the classical p42/44 MAPK-activator, increased cyclin D1 promoter activity and protein level. Overexpression 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 negatively regulated by the TAK1-MKK6-p38K pathway and positively regulated by the MKK1-p42/44 MAPK pathway.