Intracellular signaling mediated by Akt is exacerbated in the liver of transgenic mice overexpressing growth hormone.

MIQUET JG; MARTINEZ C; GONZÁLEZ L; DÍAZ ME; ZOTTA E; BARTKE A; TURYN D; SOTELO AI

Copenhagen, Dinamarca

Congreso; 44th Annual Meeting of the European Association for the Study of the Liver; 2009

European Association for the Study of the Liver

BACKGROUND AND AIMS: Akt kinase activates transcription factors that induce survival genes, as NF-kB and CREB, and is involved in cell cycle progression. GSK-3b and mTOR kinases are substrates of Akt and regulate cyclin-D1 expression. As GSK-3b promotes cyclin-D1 degradation, Akt inactivation of GSK-3b stabilizes cyclin-D1 protein, while mTOR promotes the translation of cyclin-D1 mRNA. Transgenic mice overexpressing growth hormone (GH) exhibit hepatomegaly due to hypertrophy and hyperplasia, frequently progressing to liver tumors; the preneoplasic liver pathology is similar to that present in humans at high risk of developing hepatic cancer. We have recently reported that GH-transgenic mice exhibit hepatic up-regulation of Akt and mTOR. The objective of the present work was to evaluate the participation of downstream effectors of Akt signaling in the alterations observed in GH-transgenic mice liver. METHODS: Young adult transgenic mice overexpressing GH or GH-releasing hormone were studied; non-transgenic siblings were used as controls. Protein content and phosphorylation of signaling mediators were analyzed by Western-blotting. Histological studies were performed in paraffin-embedded liver sections. RESULTS: Results obtained were similar in both types of GH-overexpressing mice. These animals exhibit high protein content of NF-kB, accompanied by phosphorylation at an activating residue. NF-kB plays an important role in cell survival and apoptosis balance and exhibits higher activity in various forms of cancer. The protein abundance of GSK-3b was also increased; however, a paralleled increase in the phosphorylation of an inactivating residue was detected. Akt, by inactivating GSK-3b, would stabilize cyclin-D1 protein. In effect, cyclin-D1 abundance is enhanced in transgenic mice. Overexpression of cyclin-D1 was found in many human cancers. In contrast, the content of CREB was decreased in transgenic mice. Loss of CREB expression was reported in tumoral cell lines. Histological analysis confirmed the preneoplasic morphological alterations in young adult transgenic mice liver. CONCLUSIONS: Akt signaling is known to be activated by growth hormone. GH-overexpressing mice exhibit alterations in this pathway that resemble those found in many tumors. As Akt is a critical regulator of cell survival, these findings suggest that this signaling cascade may be implicated in the preneoplasic liver pathology observed in GH-transgenic mice.