Transcription coactivator PBP/MED1-deficient hepatocytes are not susceptible to diethylnitrosamine-induced hepatocarcinogenesis in the mouse
نویسندگان
چکیده
Nuclear receptor coactivator [peroxisome proliferator-activated receptor-binding protein (PBP)/mediator subunit 1 (MED1)] is a critical component of the mediator transcription complex. Disruption of this gene in the mouse results in embryonic lethality. Using the PBP/MED1 liver conditional null (PBP/MED1(DeltaLiv)) mice, we reported that PBP/MED1 is essential for liver regeneration and the peroxisome proliferator-activated receptor alpha ligand Wy-14,643-induced receptor-mediated hepatocarcinogenesis. We now examined the role of PBP/MED1 in genotoxic chemical carcinogen diethylnitrosamine (DEN)-induced and phenobarbital-promoted hepatocarcinogenesis. The carcinogenic process was initiated by a single intraperitoneal injection of DEN at 14 days of age and initiated cells were promoted with phenobarbital (PB) (0.05%) in drinking water. PBP/MED1(DeltaLiv) mice, killed at 1, 4 and 12 weeks, revealed a striking proliferative response of few residual PBP/MED1-positive hepatocytes that escaped Cre-mediated deletion of PBP/MED1 gene. No proliferative expansion of PBP/MED1 null hepatocytes was noted in the PBP/MED1(DeltaLiv) mouse livers. Multiple hepatocellular carcinomas (HCCs) developed in the DEN-initiated PBP/MED1(fl/fl) and PBP/MED1(DeltaLiv) mice, 1 year after the PB promotion. Of interest is that all HCC developing in PBP/MED1(DeltaLiv) mice were PBP/MED1 positive. None of the tumors was PBP/MED1 negative implying that hepatocytes deficient in PBP/MED1 are not susceptible to neoplastic conversion. HCC that developed in PBP/MED1(DeltaLiv) mouse livers were transplantable in athymic nude mice and these maintained PBP/MED1(fl/fl) genotype. PBP/MED1(fl/fl) HCC cell line derived from these tumors expressed PBP/MED1 and deletion of PBP/MED1(fl/fl) allele by adeno-Cre injection into tumors caused necrosis of tumor cells. These results indicate that PBP/MED1 is essential for the development of HCC in the mouse.
منابع مشابه
Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity.
Peroxisome proliferator-activated receptor-binding protein (PBP), also known as thyroid hormone receptor-associated protein 220/vitamin D receptor-interacting protein 205/mediator 1, an anchor for multisubunit mediator transcription complex, functions as a transcription coactivator for nuclear receptors. Disruption of the PBP gene results in embryonic lethality around embryonic day 11.5 by affe...
متن کاملSpecific erythroid-lineage defect in mice conditionally deficient for Mediator subunit Med1.
The Mediator complex forms the bridge between transcriptional activators and the RNA polymerase II. Med1 (also known as PBP or TRAP220) is a key component of Mediator that interacts with nuclear hormone receptors and GATA transcription factors. Here, we show dynamic recruitment of GATA-1, TFIIB, Mediator, and RNA polymerase II to the β-globin locus in induced mouse erythroid leukemia cells and ...
متن کاملAblation of Coactivator Med1 Switches the Cell Fate of Dental Epithelia to That Generating Hair
Cell fates are determined by specific transcriptional programs. Here we provide evidence that the transcriptional coactivator, Mediator 1 (Med1), is essential for the cell fate determination of ectodermal epithelia. Conditional deletion of Med1 in vivo converted dental epithelia into epidermal epithelia, causing defects in enamel organ development while promoting hair formation in the incisors....
متن کاملAllantoin improves methionine-choline deficient diet-induced nonalcoholic steatohepatitis in mice through involvement in endoplasmic reticulum stress and hepatocytes apoptosis-related genes expressions
Objective(s): Non-alcoholic steatohepatitis (NASH) is defined by steatosis and inflammation in the hepatocytes, which can progress to cirrhosis and possibly hepatocellular carcinoma. However, current treatments are not entirely effective. Allantoin is one of the principal compounds in many plants and an imidazoline I receptor agonist as well. Allantoin has positive eff...
متن کاملDeleted in Liver Cancer 2 (DLC2) Was Dispensable for Development and Its Deficiency Did Not Aggravate Hepatocarcinogenesis
DLC2 (deleted in liver cancer 2), a Rho GTPase-activating protein, was previously shown to be underexpressed in human hepatocellular carcinoma and has tumor suppressor functions in cell culture models. We generated DLC2-deficient mice to investigate the tumor suppressor role of DLC2 in hepatocarcinogenesis and the function of DLC2 in vivo. In this study, we found that, unlike homologous DLC1, w...
متن کامل