Table 1.

Summary of the in vivo functions of select genes downstream from Ras during skin carcinogenesis

Gene	Mouse model	Phenotype	References
Akt	Akt1 knockout	In the DMBA/TPA model, Akt1−/− mice develop tumors with reduced yield and size	Skeen et al. 2006
	Overexpression of wild-type and constitutively active Akt1 in the basal layer of stratified epithelia using the bovine K5 promoter	Epidermal hyperplasia and hyperkeratosis, and enhanced keratinocyte proliferation in response to TPA treatment; heightened tumor susceptibility in the DMBA/TPA model	Segrelles et al. 2007
Cyclin D1	Cyclin D1 knockout	Cyclin D1−/− mice develop papillomas with increased latency and reduced incidence and yield in the DMBA/TPA model	Robles et al. 1998
Erk	Erk1 knockout	Erk1−/− mice show reduced skin inflammation and proliferation in response to TPA treatment and are tumor-resistant in the DMBA/TPA model	Bourcier et al. 2006
Fos	c-fos knockout	c-fos-deficient papillomas quickly become dry and hyperkeratinized, and fail to progress to malignancy	Saez et al. 1995
	K5-driven overexpression of a dominant-negative form of c-fos (A-Fos)	Mild alopecia and sebaceous gland hyperplasia; when subjected to chemical carcinogenesis, mice develop predominantly sebaceous adenomas	Gerdes et al. 2006
Jnk	Jnk1 and Jnk2 knockouts	In the DMBA/TPA model, Jnk1−/− mice show enhanced tumor susceptibility while Jnk2−/− mice are tumor resistant	Chen et al. 2001; She et al. 2002
Jun	c-jun knockout in the epidermis using K5-Cre	In the K5-SOS-F skin tumor model, c-jun ablation leads to smaller papillomas that show increased differentiation, possibly caused by down-regulation of EGFR	Zenz et al. 2003
	Transgenic expression of a dominant-negative form of c-jun (TAM67) in the basal epidermis (using the K14 promoter) or in the suprabasal epidermis (using the Involucrin promoter)	K14-TAM67 mice have no apparent epidermal defect but TAM67 expression in the suprabasal epidermis results in keratinocyte hyperproliferation and delayed differentiation; in the DMBA/TPA model, papillomagenesis is strongly inhibited in both transgenic mice	Young et al. 1999; Rorke et al. 2010
Mek	Overexpression of Mek1 in basal keratinocytes and hair follicle ORS using the K14 promoter	Epidermal hyperplasia and spontaneous skin tumor formation	Feith et al. 2005
	Mek2 knockout and conditional Mek1 knockout using K14-Cre	In the DMBA/TPA model, Mek1 knockout but not Mek2 knockout impedes tumorigenesis; in a mouse model of oncogenic Ras-driven skin cancer; however, both Mek1 and Mek2 (or at least one copy of each) have to be deleted to impede carcinogenesis	Scholl et al. 2009a,b
Myc	K5-Myc transgenic mice	Spontaneous papilloma and SCC development; mice are also more tumor susceptible in the DMBA/TPA model	Rounbehler et al. 2001
	K14-driven Myc overexpression	Epidermal hyperplasia, enlarged sebaceous glands, spontaneous skin lesions and stem cell loss; DMBA/TPA-treated K14-Myc mice develop tumors with reduced latency and increased yield, but these are predominantly sebaceous adenomas	Arnold and Watt 2001; Waikel et al. 2001; Honeycutt et al. 2010
Pak1	Pak1 knockout	Pak1 deficiency impedes tumor development and progression in a mouse model of KrasG12D-driven skin cancer	Chow et al. 2012
PKC	PKC-η knockout; K5-driven PKC-α overexpression; K14-driven PKC-δ or PKC-ε overexpression	In the DMBA/TPA model, PKC-η−/− and K5- PKC-α mice show enhanced tumor formation; K14-PKC-δ and K14-PKC-ε mice, on the other hand, are resistant to papilloma development; K14-PKC-ε mice also show increased de novo carcinoma formation	Reddig et al. 1999, 2000; Chida et al. 2003; Cataisson et al. 2009
Rac1	Keratinocyte-specific deletion using K5- and K14-Cre	Hair follicle (and epidermal) stem cell loss/impairment; K5-driven Rac1 ablation leads to tumor-resistance in the DMBA/TPA model, associated with a decrease in keratinocyte proliferation	Keely et al. 1997; Benitah et al. 2005; Chrostek et al. 2006; Wang et al. 2010