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Functional roles of Akt signaling in mouse skin tumorigenesis
Carmen Segrelles1, Sergio Ruiz, Paloma Perez
1Project on Cell and Molecular Biology and Gene Therapy, CIEMAT, Av. Complutense 22, E-28040 Madrid, Spain.
Abstract:
The mouse skin carcinogenesis protocol is a unique model for understanding the molecular events leading to oncogenic transformation. Mutations in the Ha-ras gene, and the presence of functional cyclin D1 and the EGF receptor, have proven to be important in this system. However, the signal transduction pathways connecting these elements during mouse skin carcinogenesis are poorly understood. This paper studies the relevance of the Akt and ERK pathways in the different stages of chemically induced mouse skin tumors. Akt activity increases throughout the entire process, and its early activation is detected prior to increased cyclin D1 expression. ERK activity rises only during the later stages of malignant conversion. The observed early increase in Akt activity appears to be due to raised PI-3K activity. Other factors acting on Akt such as ILK activation and decreased PTEN phosphatase activity appear to be involved at the conversion stage. To further confirm the involvement of Akt in this process, PB keratinocytes were transfected with Akt and subsequently injected into nude mice. The expression of Akt accelerates tumorigenesis and contributes to increased malignancy of these keratinocytes as demonstrated by the rate of appearance, the growth and the histological characteristics of the tumors. Collectively, these data provide evidence that Akt activation is one of the key elements during the different steps of mouse skin tumorigenesis.
Insights
The Akt pathway is crucial in mouse skin tumor development, activating early and promoting malignancy. Its activation, linked to PI-3K, precedes cyclin D1 increases and accelerates tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- Carcinogenesis
Background:
- Mouse skin carcinogenesis is a key model for studying oncogenic transformation.
- Signal transduction pathways in skin carcinogenesis are not fully understood.
- Key elements include Ha-ras mutations, cyclin D1, and EGF receptor.
Purpose of the Study:
- To investigate the roles of Akt and ERK pathways in chemically induced mouse skin tumors.
- To elucidate the temporal activation of these pathways during carcinogenesis.
- To confirm the functional significance of Akt in skin tumorigenesis.
Main Methods:
- Analysis of Akt and ERK pathway activity at different stages of skin tumor development.
- Investigation of upstream regulators of Akt, including PI-3K, ILK, and PTEN.
- Experimental validation using Akt-transfected keratinocytes in nude mouse models.
Main Results:
- Akt activity increased throughout carcinogenesis, preceding cyclin D1 elevation.
- ERK activity was elevated only in later stages of malignant conversion.
- Early Akt activation was linked to increased PI-3K activity, with ILK and PTEN involvement at conversion.
- Akt-transfected keratinocytes accelerated tumor formation and increased malignancy in vivo.
Conclusions:
- Akt activation is a critical event in mouse skin tumorigenesis.
- Akt plays a significant role in both early and late stages of tumor development.
- Targeting the Akt pathway may offer therapeutic strategies for skin cancer.