Mice hemizygous for this "K14-ER:Ras" transgene are viable and fertile, with expression of the ER:Ras fusion protein (constitutively active G12V mutant form of the catalytic domain of human H-ras (H-rasV12) fused at its amino terminal with the G525R mutant murine estrogen receptor ligand binding domain (ER^TM)) directed to epidermis by the human keratin 14 promoter. Because of the ER^TM region of the fusion protein, ER:Ras is restricted to the cytoplasm and the biochemical activity of the ER:Ras fusion gene can be induced following tamoxifen administration. For example, prolonged (4 weeks) induction of human H-Ras^G12V activity promotes the undifferentiated, proliferative phenotypic characteristics observed in epidermal cancer; including hyperplasia, increased mitotic index, decreased expression of differentiation markers and increased expression of beta-1 and beta-4 integrin subunits. H-Ras^G12V-induced skin abnormalities were entirely reversed within one month after 4OHT cessation. These mice have a similar 4OHT-inducible skin phenotype as the transgenic mice expressing human Raf-1[DD] (Stock No. 006661) or human Mek1^R4F (Stock No. 006822), and may be useful in studies of the Ras/Raf/MEK/ERK cell proliferation and differentiation pathway, as well as to elucidate cellular events preceding skin cancer cell transformation.

The G525R mutant murine estrogen receptor ligand binding domain (ER^TM) does not bind its natural ligand (17β-estradiol) at physiological concentrations; but will bind the synthetic estrogen receptor ligands 4-hydroxytamoxifen (OHT or tamoxifen) and, with lesser sensitivity, ICI 182780. Restricted to the cytoplasm, ER^TM fusion proteins can only gain access to the nuclear compartment after exposure to tamoxifen. To counteract the mixed estrogen agonist effects of tamoxifen injections, which can result in late fetal abortions in pregnant mice, progesterone may be coadministered.