IKK-β缺陷小鼠的胚胎致死、肝脏退化及核因子κB激活受损

Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice.

作者信息

Tanaka M, Fuentes M E, Yamaguchi K, Durnin M H, Dalrymple S A, Hardy K L, Goeddel D V

机构信息

Tularik, Incorporated, South San Francisco, California 94080, USA.

出版信息

Immunity. 1999 Apr;10(4):421-9. doi: 10.1016/s1074-7613(00)80042-4.

DOI:10.1016/s1074-7613(00)80042-4

PMID:10229185

Abstract

IkappaB kinase-alpha and -beta (IKK-alpha and IKK-beta), the catalytic subunits of the IKK complex, phosphorylate IkappaB proteins on specific serine residues, thus targeting IkappaB for degradation and activating the transcription factor NF-kappaB. To elucidate the in vivo function of IKK-beta, we generated IKK-beta-deficient mice. The homozygous mouse embryo dies at approximately 14.5 days of gestation due to liver degeneration and apoptosis. IKK-beta-deficient embryonic fibroblasts have both reduced basal NF-kappaB activity and impaired cytokine-induced NF-kappaB activation. Similarly, basal and cytokine-inducible kinase activities of the IKK complex are greatly reduced in IKK-beta-deficient cells. These results indicate that IKK-beta is crucial for liver development and regulation of NF-kappaB activity and that IKK-alpha can only partially compensate for the loss of IKK-beta.

摘要

IκB激酶α和β（IKK-α和IKK-β）是IKK复合物的催化亚基，可使IκB蛋白特定丝氨酸残基磷酸化，从而促使IκB降解并激活转录因子NF-κB。为阐明IKK-β在体内的功能，我们构建了IKK-β基因缺陷小鼠。纯合子小鼠胚胎在妊娠约14.5天时因肝脏变性和凋亡而死亡。IKK-β基因缺陷的胚胎成纤维细胞基础NF-κB活性降低，且细胞因子诱导的NF-κB激活受损。同样，IKK-β基因缺陷细胞中IKK复合物的基础激酶活性和细胞因子诱导的激酶活性也大幅降低。这些结果表明，IKK-β对肝脏发育和NF-κB活性调节至关重要，且IKK-α只能部分补偿IKK-β的缺失。