Functional roles of Akt signaling in mouse skin tumorigenesis

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 di erent 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 con®rm 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 di erent steps of mouse skin tumorigenesis.

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

“…As AKT activation provides a key survival signal for cells to evade apoptosis, the enhanced AKT activation may play a crucial role in acquired apoptotic resistance and perhaps malignant transformation induced by chronic UVA exposure. In the two-stage, chemical models of mouse skin carcinogenesis, one of the key elements is thought to be increased AKT signaling (Segrelles et al, 2002). Specifically, the overexpression of AKT both accelerates tumor formation and contributes to tumor progression (Segrelles et al, 2002).…”

“…In the two-stage, chemical models of mouse skin carcinogenesis, one of the key elements is thought to be increased AKT signaling (Segrelles et al, 2002). Specifically, the overexpression of AKT both accelerates tumor formation and contributes to tumor progression (Segrelles et al, 2002). PTEN is one of the tumor suppressor genes commonly mutated in various advanced human cancers including glioblastomas, as well as prostate, breast, endometrial and renal cancers (Stambolic et al, 1998).…”

Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

“…In mice, Akt activation promotes tumor formation (Segrelles et al, 2002;Skeen et al, 2006) and, in humans, Akt activation by loss of PTEN corresponds to increased formation of skin lesions including benign tumors (Cowden's disease). Using immunofluorescent staining of cryosections, we could detect increased Akt activation following DMBA/TPA treatment in suprabasal, but not in basal keratinocytes.…”

Physiological Functions of Pten in Mouse Tissues.

“…Other evidence suggests that PKB/Akt may be a key molecule regulating the onset of skin carcinogenesis in mice. The transplantation of keratinocytes overexpressing PKB/Akt results in highly aggressive skin tumors, and PKB/Akt activation is one of the first events in the chemical induction of skin tumors (Segrelles et al, 2002). Thus, the onset of tumors in k5Pten flox/flox mice may be caused primarily by cellular hyperproliferation and/or apoptotic resistance induced by PI3K and PKB/Akt hyperactivation, with a contribution by deregulated ERK activation.…”

“…Transgenic animals overexpressing IGF-1 also show accelerated hair growth (Bol et al, 1997), and mice lacking IGF-1R exhibit hypoplastic skin (Liu et al, 1993). Since each of EGFR, IGF-R and Ras triggers PI3K signaling, and decreased Pten activity contributes to the malignant conversion stage in chemically-induced mouse skin cancers (Segrelles et al, 2002), we generated keratinocyte-specific Pten-deficient mice (k5CrePten flox/flox mice) by crossing Pten flox mice to K5-Cre transgenic mice (Suzuki et al, in revision).…”