Deregulated expression of E2F1 induces hyperplasia and cooperates with ras in skin tumor development

Abstract

In cell culture studies, overexpression of the E2F1 transcription factor has been shown to stimulate proliferation, induce apoptosis, and cooperate with an activated ras gene to oncogenically transform primary rodent cells. To study the e ect of increased E2F1 activity on epithelial growth and tumorigenesis in vivo, transgenic mice expressing E2F1 under the control of a keratin 5 (K5) promoter were generated. Expression of E2F1 in the epidermis results in hyperplasia but does not inhibit terminal di erentiation. In a transgenic line expressing high levels of E2F1, mice have decreased hair growth likely as a result of aberrant apoptosis in developing hair follicles. Coexpression of a cyclin D1 transgene with E2F1 augments epidermal hyperplasia and further disrupts hair follicle development suggesting that hypophosphorylated Rb antagonizes the proliferative and apoptotic-promoting activities of E2F1. Finally, the E2F1 transgene is found to cooperate with a v-Ha-ras transgene to induce skin tumors in double transgenic animals. These ®ndings con®rm that many of the activities ascribed to E2F1 through in vitro studies can be reproduced in vivo and demonstrate for the ®rst time that deregulated E2F activity can contribute to tumor development.

E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes

“…In this study we provide evidence that E2F-1 maintains the proliferative state of keratinocytes and actively suppresses di erentiation. A recent study reported that deregulated expression of E2F-1 in the mouse epidermis induced hyperplasia and hyperproliferation but did not inhibit terminal di erentiation (Pierce et al, 1998). However, in this transgenic model, E2F-1 was expressed from the keratin 5 promoter, which is normally only expressed in the basal layer of the epidermis and is`switched o ' when cells move into the suprabasal layer.…”

“…For instance, E2F-1 has been reported to (i) be oncogenic (Johnson et al, 1994;Pierce et al, 1998); (ii) act as a tumour suppressor (Yamasaki et al, 1996); (iii) promote apoptosis (Shan and Lee, 1994;Qin et al, 1994); (iv) transform cells (Yang and Sladek, 1995;Sladek, 1996); or (v) block di erentiation (Wang et al, 1995;Guy et al, 1996). The most likely explanation for these opposing e ects may be attributed to cell type-restricted functions for E2F-1.…”

“…Such cell type-speci®city highlights the importance of studying E2F action in the context of a speci®c tissue type of biological relevance. In mouse keratinocytes, overexpression of E2F-1 under the proliferation-associated Keratin 5 promoter resulted in hyperkeratosis in the interfollicular epidermis, whilst a decrease in hair follicle number was attributed to an increase in apoptosis in the developing hair (Pierce, et al, 1998). This suggests that even within the same cell type, E2F-1 function may vary dependent on the di erentiation-speci®c role of the constituent cell type.…”

Phosphorylation by p38 MAP kinase is required for E2F1 degradation and keratinocyte differentiation

“…Similarly, loss of E2F1 expression results in altered responses to ultraviolet damage (Berton et al, 2005). Reciprocally, chemically induced skin carcinogenesis is associated with increased E2F1 expression (Balasubramanian et al, 1999), and overexpression of E2F1 in the epidermis of transgenic mice results in tumor formation (Pierce et al, 1998). E2F1 activity is regulated by transcriptional and posttranslational mechanisms.…”

Novel link between E2F and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F

“…Ectopic expression of E2F1 leads to apoptosis in tissue culture cells [3][4][5] and transgenic mice. [6][7][8] Moreover, a physiological role for E2F1-mediated apoptosis is suggested by the observation that mice deficient in E2F1 have an excess of mature T cells due to a defect in thymocyte apoptosis. 9 E2F1-induced apoptosis occurs via both p53-dependent and -independent pathways.…”