Expression of cyclin D1 in epithelial tissues of transgenic mice results in epidermal hyperproliferation and severe thymic hyperplasia.

Abstract

To study the involvement of cyclin Dl in epithelial growth and differentiation and its putative role as an oncogene in skin, transgenic mice were developed carrying the human cyclin Dl gene driven by a bovine keratin 5 promoter. As expected, all squamous epithelia including skin, oral mucosa, trachea, vaginal epithelium, and the epithelial compartment of the thymus expressed aberrant levels ofcyclin Dl. The rate of epidermal proliferation increased dramatically in transgenic mice, which also showed basal cell hyperplasia. However, epidermal differentiation was unaffected, as shown by normal growth arrest of newborn primary keratinocytes in response to high extracellular calcium. Moreover, an unexpected phenotype was observed in the thymus. Transgenic mice developed a severe thymic hyperplasia that caused premature death due to cardio-respiratory failure within 4 months of age. By 14 weeks, the thymi of transgenic mice increased in weight up to 40-fold, representing 10% of total body weight. The hyperplastic thymi had normal histology revealing a well-differentiated cortex and medulla, which supported an apparently normal T-cell developmental program based on the distribution of thymocyte subsets. These results suggest that proliferation and differentiation of epithelial cells are under independent genetic controls in these organs and that cyclin Dl can modulate epithelial proliferation without altering the initiation of differentiation programs. No spontaneous development of epithelial tumors or thymic lymphomas was perceived in transgenic mice during their first 8 months of life, although they continue under observation. This model provides in vivo evidence of the action of cyclin DI as a pure mediator of proliferation in epithelial cells.

Deregulated expression of cell-cycle proteins during premalignant progression in SENCAR mouse skin

“…Overexpression of cyclin D1 in the mammary glands of transgenic mice leads to hyperplasia and tumor formation (Wang et al, 1994). Also, our previous results have shown that overexpression of cyclin D1 under the control of the keratin 5 promotor leads to epidermal hyperproliferation and thymic hyperplasia (Robles et al, 1996).…”

Cyclin A is a prognostic indicator in early stage breast cancer with and without tamoxifen treatment

“…Introduction of these genes in murine fibroblasts contributes to cellular transformation, and genetic alterations leading to increased expression of these genes are frequently observed in breast cancer (Quelle et al, 1993;Galaktionov et al, 1995;Michalides, 1999;Cangi et al, 2000). Mice transgenic for cyclin D1 are prone to tumour development, the type of tumour being dependent on the enhancer sequence used to construct the cyclin D1 transgene (Bodrug et al, 1994;Wang et al, 1994;Robles et al, 1996). However, neither overexpression of cyclin D1 or of cdc25A was found to be an independent indicator of prognosis in early stage breast cancer (Michalides et al, 1996; van Diest et al, 1997; Cangi Leong et al, 2000).…”

Differential expression and functionally co-operative roles for the retinoblastoma family of proteins in epidermal differentiation

“…Dashed line denote the epidermal-dermal border; sb, stratum basal; ss, stratum spinous; sg stratum granulosum; sc, stratum corneum. Bar = 50 mM transgenic mice in which the expression of these viral proteins (Missero et al, 1993;Arbeit et al, 1994;Auewarakul et al, 1994) or cyclin D1 (Robles et al, 1996), which is involved in the functional incativation of Rb proteins (Weinberg, 1995), was targeted to the skin. Our results showing the di erential expression of the Rb family of proteins both during in vitro di erentiation (Figure 1), and in epidermis in vivo (Figures 2 and 3), strongly suggest speci®c functions for these molecules during epidermal di erentiation.…”

“…However, the reduced ability to di erentiate displayed by human keratinocytes immortalized by the forced expression of viral proteins that bind and inactivate the pRb family, such as T antigen (Taylor-Papadimitriou et al, 1982;Banks-Schlegel and Howley, 1983), HPV E7 (McCance et al, 1988;Hudson et al, 1990) and E1A (Barrandon et al, 1989), together with the requirement of the HPV E7 protein in the etiology of certain human skin pathologies (Zur Hausen, 1991), strongly suggest the involvement of pRb members in epidermal proliferation and differentiation. This is reinforced by the alterations observed in transgenic mice in which the expression of these viral proteins (Missero et al, 1993;Arbeit et al, 1994;Auewarakul et al, 1994) or cyclin D1 (Robles et al, 1996) is targeted to the epidermis.…”