Genetic ablation of CCAAT/Enhancer binding protein alpha in epidermis reveals its role in suppression of epithelial tumorigenesis

CCAAT/enhancer binding protein alpha (C/EBP alpha) is a basic leucine zipper transcription factor that inhibits cell cycle progression and regulates differentiation in various cell types. C/EBP alpha is inactivated by mutation in acute myeloid leukemia (AmL) and is considered a human tumor suppressor in AML. Although C/EBP alpha mutations have not been observed in malignancies other than AML, greatly diminished expression of C/EBP alpha occurs in numerous human epithelial cancers including lung, liver, endometrial, skin, and breast, suggesting a possible tumor suppressor function. However, direct evidence for C/EBP alpha as an epithelial tumor suppressor is lacking due to the absence of C/EBP alpha mutations in epithelial tumors and the lethal effect of C/EBP alpha deletion in mouse model systems. To examine the function of C/EBP alpha in epithelial tumor development, an epidermal-specific C/EBP alpha knockout mouse was generated. The epidermal-specific C/EBPa knockout mice survived and displayed no detectable abnormalities in epidermal keratinocyte proliferation, differentiation, or apoptosis, showing that C/EBP alpha is dispensable for normal epidermal homeostasis. In spite of this, the epidermal-specific C/EBP(x knockout mice were highly susceptible to skin tumor development involving oncogenic Ras. These mice displayed decreased tumor latency and striking increases in tumor incidence, multiplicity, growth rate, and the rate of malignant progression. Mice hemizygous for C/EBP alpha displayed an intermediate-enhanced tumor phenotype. Our results suggest that decreased expression of C/EBP alpha. contributes to deregulation of tumor cell proliferation. C/EBP alpha had been proposed to block cell cycle progression through inhibition of E2F activity. We observed that C/EBPa blocked Ras-induced and epidermal growth factor-induced E2F activity in keratinocytes and also blocked Ras-induced cell transformation and cell cycle progression. Our study shows that C/EBP alpha is dispensable for epidermal homeostasis and provides genetic evidence that C/EBP alpha is a suppressor of epithelial tumorigenesis.

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