title: Predisposition to apoptosis in keratin 8-null liver is related to inactivation of NF-κB and SAPKs but not decreased c-Flip.
abstract: Keratin 8 and 18 (K8/K18) are major intermediate filament proteins of liver hepatocytes. They provide mechanical and nonmechanical stability, thereby protecting cells from stress. Hence, K8-null mice are highly sensitive to Fas-mediated liver cell apoptosis. However, the role of c-Flip protein in K8-null related susceptibility to liver injury is controversial. Here we analyzed c-Flip protein expression in various K8 or K18 null/mutant transgenic livers and show that they are similar in all analyzed transgenic livers and that previously reported c-Flip protein changes are due to antibody cross-reaction with mouse K18. Furthermore, analysis of various apoptosis- or cell survival-related proteins demonstrated that inhibition of phosphorylation of NF-κB and various stress activated protein kinases (SAPKs), such as p38 MAPK, p44/42 MAPK and JNK1/2, is related to the higher sensitivity of K8-null hepatocytes whose nuclear NF-κB is rapidly depleted through Fas-mediated apoptosis. Notably, we found that NF-κB and the studied protein kinases are associated with the K8/K18 complex and are released upon phosphorylation. Therefore, interaction of keratins with cell survival-related protein kinases and transcription factors is another important factor for hepatocyte survival.
authors.affiliation: Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University , Seoul 120-749 , Korea.
authors.forename: Jongeun
authors.initials: J
authors.lastname: Lee
authors.forename: Kwi-Hoon
authors.initials: KH
authors.lastname: Jang
authors.forename: Hakhyun
authors.initials: H
authors.lastname: Kim
authors.forename: Younglan
authors.initials: Y
authors.lastname: Lim
authors.forename: Sujin
authors.initials: S
authors.lastname: Kim
authors.forename: Han-Na
authors.initials: HN
authors.lastname: Yoon
authors.forename: In Kwon
authors.initials: IK
authors.lastname: Chung
authors.forename: Jürgen
authors.initials: J
authors.lastname: Roth
authors.forename: Nam-On
authors.initials: NO
authors.lastname: Ku
keywords: Apoptosis; Intermediate filaments; Keratin; Liver; NF-κB; SAPK; c-Flip