Related Experiment Videos
Oncogenic transformation induced by membrane-targeted Akt2 and Akt3
I Mende1, S Malstrom, P N Tsichlis
1Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California CA 92037, USA.
Abstract:
The kinases Akt2, Akt3 and their myristylated variants, Myr-Akt2 and Myr-Akt3 were expressed by the RCAS vector in chicken embryo fibroblasts (CEF). Myr-Akt2 and Myr-Akt3 were strongly oncogenic, inducing multilayered foci of transformed cells. In contrast, wild-type Akt2 and Akt3 were only poorly transforming, their efficiencies of focus formation were more than 100-fold lower; foci appeared later and showed less multilayering. Addition of the myristylation signal not only enhanced oncogenic potential but also increased kinase activities. Myr-Akt2 and Myr-Akt3 also induced hemangiosarcomas in the animal, whereas wild type Akt2 and Akt3 were not oncogenic in vivo. Furthermore, Akt2, driven by the lck (lymphocyte specific kinase) promoter in transgenic mice, induced lymphomas. The oncogenic effects of Akt2 and Akt3 described here are indistinguishable from those of Akt1. The downstream targets relevant to oncogenic transformation are therefore probably shared by the three Akt kinases.
Insights
Myristylation strongly enhances the oncogenic potential of Akt2 and Akt3 kinases, leading to increased transformation and tumor formation in vivo. These findings suggest shared downstream targets among Akt kinases in cancer development.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- The serine/threonine-protein kinase Akt (also known as Protein Kinase B) is a crucial regulator of cell survival, proliferation, and metabolism.
- Aberrant activation of Akt signaling is frequently observed in various human cancers, highlighting its role in oncogenesis.
Purpose of the Study:
- To investigate the role of Akt2 and Akt3 kinases, and their myristylated variants, in cellular transformation and tumor development.
- To compare the oncogenic potential of myristylated Akt2/Akt3 with their wild-type counterparts.
Main Methods:
- Expression of wild-type and myristylated Akt2 and Akt3 (Myr-Akt2, Myr-Akt3) in chicken embryo fibroblasts (CEF) using the RCAS vector.
- Assessment of focus-forming ability and cellular transformation in vitro.
- Induction of tumors in animal models (hemangiosarcomas and lymphomas) to evaluate oncogenicity in vivo.
Main Results:
- Myr-Akt2 and Myr-Akt3 exhibited significantly enhanced oncogenic potential compared to wild-type Akt2 and Akt3, inducing rapid and multilayered foci of transformed cells.
- Myristylation increased kinase activity and oncogenic potency.
- Myr-Akt2 and Myr-Akt3 induced hemangiosarcomas in vivo, while wild-type Akt2/Akt3 were not oncogenic.
- Akt2 expression driven by the lck promoter in transgenic mice led to lymphoma development.
- The oncogenic effects of Akt2 and Akt3 were comparable to Akt1, suggesting shared downstream pathways.
Conclusions:
- Myristylation is a critical modification that significantly potentiates the oncogenic activity of Akt2 and Akt3.
- Akt2 and Akt3 play substantial roles in oncogenesis, potentially through pathways overlapping with Akt1.
- Targeting shared downstream effectors of Akt kinases may offer therapeutic strategies for various cancers.