Abstract
Myc is activated in many tumours, yet, paradoxically, stimulates differentiation in mammalian epidermis. To test whether the epidermis responds differently to different levels of Myc, we treated K14MycER transgenic mice with a range of concentrations of the inducing agent, 4-hydroxy-tamoxifen (4OHT). Proliferation was stimulated at all levels of Myc activity; sebocyte differentiation was stimulated at low and intermediate levels; and interfollicular epidermal differentiation at intermediate and high levels. Mutational inactivation of the Myc p21 activated kinase 2 (PAK2) phosphorylation sites increased Myc activity and further enhanced epidermal differentiation. We conclude that Myc induced differentiation acts as a fail-safe device to prevent uncontrolled proliferation and neoplastic conversion of epidermal stem cells expressing high levels of Myc.
Highlights
The most common forms of cancer are basal cell carcinoma and squamous cell carcinoma, non-melanoma tumours of the epidermis
Differential activation of MycER by different 4OHT concentrations We treated keratinocyte lines established from K14MycER epidermis overnight with 4OHT concentrations ranging from 10 to 200 nM, and examined nuclear accumulation of MycER by immunofluorescence staining with an anti-estrogen receptor (ER) antibody
To confirm that there was dose-dependent activation of myelocytomatosis viral oncogene homologue (Myc), we transfected wild type and K14MycER keratinocytes with a synthetic Myc reporter (M4) in which luciferase is expressed under the control of a SV40 promoter enhanced by four Myc specific E-boxes, or mM4, a reporter in which the E-boxes have been mutationally inactivated (Laherty et al, 1997)
Summary
The most common forms of cancer are basal cell carcinoma and squamous cell carcinoma, non-melanoma tumours of the epidermis They are believed to arise when epidermal stem cells acquire oncogenic lesions that result in uncontrolled proliferation and impaired differentiation (Janes & Watt, 2006). The lineages that are expanded on Myc activation are those that are normally controlled by Blimp and Lrig, namely SG and IFE (Arnold & Watt, 2001; Waikel et al, 2001; Watt et al, 2008) These observations have led to the hypothesis that Myc-induced differentiation is a fail-safe device to prevent uncontrolled proliferation, and tumour formation, by the epidermal stem cell compartment (Jensen & Watt, 2006; Jensen et al, 2009; Watt & Jensen, 2009). This provides a more refined approach to controlling Myc levels than that of comparing homozygous and heterozygous transgenic mice (Murphy et al, 2008)
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