Abstract
Aberrant activation of the phosphoinositide-3-kinase (PI3K)/PTEN/Akt pathway, leading to increased proliferation and decreased apoptosis, has been implicated in several human pathologies including cancer. Our previous data have shown that Akt-mediated signaling is an essential mediator in the mouse skin carcinogenesis system during both the tumor promotion and progression stages. In addition, overexpression of Akt is also able to transform keratinocytes through transcriptional and posttranscriptional processes. Here, we report the consequences of the increased expression of Akt1 (wtAkt) or constitutively active Akt1 (myrAkt) in the basal layer of stratified epithelia using the bovine keratin K5 promoter. These mice display alterations in epidermal proliferation and differentiation. In addition, transgenic mice with the highest levels of Akt expression developed spontaneous epithelial tumors in multiple organs with age. Furthermore, both wtAkt and myrAkt transgenic lines displayed heightened sensitivity to the epidermal proliferative effects of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and heightened sensitivity to two-stage skin carcinogenesis. Finally, enhanced susceptibility to two-stage carcinogenesis correlated with a more sustained proliferative response following treatment with TPA as well as sustained alterations in Akt downstream signaling pathways and elevations in cell cycle regulatory proteins. Collectively, the data provide direct support for an important role for Akt signaling in epithelial carcinogenesis in vivo, especially during the tumor promotion stage.
Highlights
Akt is a 60-kDa serine/threonine kinase capable of modulating numerous processes in the cell, including cell survival andNote: Supplementary data for this article are available at Cancer Research Online.Data generated over the past decade have shown that the activation of Akt kinases is frequent in a wide number of human solid tumors and hematologic malignancies
We have shown that Akt is a key molecule in insulin-like growth factor-I (IGF-I)–mediated mouse skin tumor promotion [7]
We have shown that deregulation of Akt activity mediated through increased expression of either the wildtype form or an activated form of Akt in the epidermis of transgenic mice leads to an increase in epidermal proliferation, which led to alterations in epidermal differentiation and hyperplasia
Summary
Akt is a 60-kDa serine/threonine kinase capable of modulating numerous processes in the cell, including cell survival andNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).Data generated over the past decade have shown that the activation of Akt kinases is frequent in a wide number of human solid tumors and hematologic malignancies (reviewed in ref. 3). Akt is a 60-kDa serine/threonine kinase capable of modulating numerous processes in the cell, including cell survival and. Data generated over the past decade have shown that the activation of Akt kinases is frequent in a wide number of human solid tumors and hematologic malignancies Several mouse models have contributed to our understanding that aberrant Akt signaling plays a predominant role in malignant transformation in vivo, either alone or in cooperation with other genetic alterations [4,5,6]. Diverse tumor promoters have been shown to activate epidermal Akt following topical treatment through activation of the EGFr [8]. Using cultured cell systems, we provided evidence indicating that Akt may function differently in epidermal tumors than in other tissues through transcriptional and posttranscriptional mechanisms, which have several parallels with human head and neck squamous cell carcinomas Using cultured cell systems, we provided evidence indicating that Akt may function differently in epidermal tumors than in other tissues through transcriptional and posttranscriptional mechanisms, which have several parallels with human head and neck squamous cell carcinomas (SCC; ref. 11)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
