Abstract
AimsTo investigate the role and the regulation of the long variant of myeloid cell leukemia-1 protein (Mcl-1L) during liver regeneration.BackgroundLiver regeneration is an important phenomenon after liver injury. The rat partial hepatectomy (PH) model was used to characterize liver regeneration and Mcl-1L expression after PH.MethodsMale Wistar rats were subjected to 70% PH. The expression of mcl-1L mRNA was determined by quantitative RT-PCR, and protein levels were analyzed by Western blot analysis and immunohistochemistry during liver regeneration. Functional evaluations of Mcl-1L were tested using chemical inhibition (flavopiridol), genetic inhibition (siRNA) of Mcl-1L production, and by assaying for annexin V levels and DNA ladder formation. Serum IL-6 levels were determined by enzyme immunoassays; signal transduction of IL-6-regulated Mcl-1L expression was verified by chemical inhibitors and decoy double-stranded oligodeoxynucleotides.ResultsHigh levels of Mcl-1L were observed in remnant tissue at 4 h after PH. Administration of flavopiridol decreased Mcl-1L accumulation and also inhibited liver regeneration. IL-6 administration promoted the accumulation of Mcl-1L in rat hepatocytes, an effect that was impaired by siRNA treatments that reduced Mcl-1L production. Chemical inhibition and decoy oligonucleotide competition demonstrated that IL-6-induced Mcl-1L production required signaling mediated by JAK kinase, phosphoinositide 3-kinase (PI3K), and cAMP response-element-binding (CREB) proteins.ConclusionMcl-1L is an anti-apoptotic protein induced during liver regeneration after PH in rats. The expression of Mcl-1L is induced by IL-6 through the JAK/PI3K/Akt/CREB signaling pathway. Chemotherapy drugs that depend on Mcl-1L- or IL-6-related signaling should be considered carefully before use in patients undergoing hepatectomy for malignant tumor resection.
Highlights
Liver regeneration is an important phenomenon after liver injury, and the reproducibility of the partial hepatectomy (PH) model has made it the preferred approach for studies of liver regeneration [1]
IL-6 administration promoted the accumulation of Mcl-1L in rat hepatocytes, an effect that was impaired by siRNA treatments that reduced Mcl-1L production
Chemical inhibition and decoy oligonucleotide competition demonstrated that IL-6-induced Mcl-1L production required signaling mediated by JAK kinase, phosphoinositide 3-kinase (PI3K), and cAMP response-element-binding (CREB) proteins
Summary
Liver regeneration is an important phenomenon after liver injury, and the reproducibility of the partial hepatectomy (PH) model has made it the preferred approach for studies of liver regeneration [1]. The accumulation of Bcl-2 family members during liver regeneration suggested cell cycle-dependent regulation as well as a physiological role for apoptosis-modulating proteins during growth and proliferation [8]–[][10]. Myeloid cell leukemia-1 (Mcl-1), a member of the Bcl-2 family, inhibits apoptosis by inhibiting Ca2+ signals within mitochondria [10]. Mcl-1 knockout mice exhibit liver damage and increased apoptotic susceptibility of murine hepatocytes, suggesting that Mcl-1 is a crucial anti-apoptotic factor in the liver [14]. Other studies confirm that Mcl-1 and Bcl-xL cooperatively maintain the integrity of hepatocytes in developing and adult murine livers [9]. The rat partial hepatectomy (PH) model was used to characterize liver regeneration and Mcl-1L expression after PH
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