Suprabasal Induction of Ornithine Decarboxylase in Adult Mouse Skin Is Sufficient to Activate Keratinocytes

Abstract

To study the effects of de novo induction of ornithine decarboxylase (ODC) activity in adult, quiescent skin, we generated transgenic mice in which the suprabasal expression of an inducible form of the ODC protein fused to a modified estrogen receptor ligand-binding domain (ODCER) is driven by an involucrin promoter. After topical treatment with the inducing agent 4-hydroxytamoxifen (4OHT), ODC activity and putrescine levels were dramatically increased in the epidermis but not in the dermis of transgenic mice. 4OHT treatment stimulated both proliferation as measured by bromodeoxyuridine incorporation in basal epidermal cells and differentiation shown by increased expression of differentiation markers. Furthermore, induction of ODC activity did not rescue primary epidermal keratinocyte cultures isolated from ODCER2 mice from a calcium-triggered DNA synthesis block, as measured by [3H]thymidine incorporation. In vivo induction of epidermal ODC enzyme activity significantly stimulated the vascularization of ODCER transgenic skin. Increased expression of interleukin-1beta and keratin 6, markers of keratinocyte activation seen in wound healing, was also observed in 4OHT-treated transgenic skin. These results suggest that de novo suprabasal induction of ODC activity in adult mouse skin activates keratinocytes and stimulates vascularization in the dermal layer in a manner similar to skin undergoing wound healing.

Polyamines and nonmelanoma skin cancer

“…Interestingly, ODC overexpression targeted to the suprabasal layer of nontumor-bearing ODCER transgenic epidermis appears to affect other cell subpopulations in the skin, resulting in increased proliferation in the basal cells of the epidermis and activation of the underlying stromal layer with neovascularization and increased synthesis of extracellular matrix proteins in a manner similar to wound repair in skin (Lan et al, 2005). Increased vascularization of the skin has been reported in K6/ODC transgenic mice as well (Lan et al, 2000).…”

“…These sustained high levels of putrescine lead to alopecia, the development of follicular dermal cysts, increased nail growth, and skin wrinkling. With regard to tumor development, the targeted expression of ODC to the skin also increases the susceptibility of these mice to skin tumor formation following a variety of initiating events including carcinogens (O'Brien et al, 1997;Chen et al, 2000), UV irradiation (Ahmad et al, 2001), and oncogenes (Smith et al, 1998;Tang et al, 2004;Lan et al, 2005). The treatment of newborn or adult K6/ODC transgenic mice with a single topical application of the carcinogen 7, 12-dimethylbenz[a]anthracene (DMBA) yields papilloma formation six to eight weeks later without the use of tumor promoting agents (O'Brien et al, 1997;Peralta Soler et al, 1998).…”

“…Bi-transgenic mice expressing both skin-targeted ODC and the v-Ha-ras oncogene develop spontaneous keratoacanthomas and squamous cell carcinomas, whereas no tumors develop in the mono-transgenic mice (Smith et al, 1998;Lan et al, 2005). On the other hand, basal cell carcinomas develop in mice that are both heterozygous null for the patched tumor suppressor gene and overexpressing ODC in follicular cells (Tang et al, 2004).…”

“…Since it is not known how the abnormal skin phenotype of the K6/ODC transgenic mouse may contribute to changes in proliferation and tumorigenesis, a transgenic mouse model with a normal skin phenotype in which an inducible form of ODC is targeted to suprabasal epidermal cells by an involucrin promoter was generated (Lan et al, 2005). De novo induction of suprabasal epidermal ODC activity in ODCER transgenic mice increases both proliferation in the basal layer of the epidermis as well as epidermal differentiation (Lan et al, 2005). Suprabasal cells in intact, normal adult skin are no longer proliferating and are committed to terminally differentiate.…”

“…This proliferation control is disrupted in skin tumorigenesis, and cycling cells that express high levels of ODC can be found also in suprabasal layers of skin tumors (Gilmour et al, 1986;Smith et al, 1998). However, induction of only ODC activity without any oncogene activation does not rescue primary epidermal keratinocyte cultures isolated from ODCER mice from a calcium-triggered DNA synthesis block in cells committed to terminally differentiate (Lan et al, 2005). Altered keratinocyte differentiation and an increased proliferation index has also been reported with SSAT overexpression and increased putrescine levels in UKU 165b transgenic mice (Pietila et al, 2005).…”