Diacylglycerol Signaling

15 Transgenic Mouse Models to Investigate Functional Specificity of Protein Kinase C
The metastatic potential of a transformed keratinocyte appeared to inversely
correlate with the differentiation potential of that keratinocyte in the limited number
of tumors studied to date. This conclusion was based on the location of invasion
and pathological categorization of PKCe transgenic mouse carcinoma compared
with wild-type mouse carcinoma. Bulge keratinocytes are located near the sebaceous
gland within the hair follicle. Evidence suggests that these cells appear to be
the stem or progenitor cells for both the hair follicle and epidermis and, therefore,
would be in a less-differentiated state than epidermal cells (Jansen et al. 2001b).
These properties may increase the metastatic potential of these cells. The carcinomas
of PKCe transgenic mice that led to metastases were also less differentiated
than carcinomas from wild-type mice. Evidence suggested that malignant cells that
invaded from the hair follicle were less differentiated and had a higher metastatic
potential than cells that invaded from the epidermis.
15.2.2.5 Possible Mechanisms by Which PKCe Sensitizes Skin
to the Development of SCC
PKCe, when get activated either via direct binding to TPA or indirectly by UVR
treatment, mediates two potential signals leading to inhibition of apoptosis (Basu
and Sivaprasad 2007; Verma et al. 2006) and induction of cell proliferation
(Wheeler et al. 2004, 2005).
15.2.2.6 PKCe Overexpression in Transgenic Mice Inhibits UVR-Induced
Formation of Sunburn Cells
PKCe overexpression in transgenic mice, as compared with their wild-type littermates,
reduced the appearance of sunburn cells. Sunburn cells are DNA-damaged
keratinocytes undergoing apoptosis (Hill et al. 1999; Lu et al. 2007; Ziegler et al.
1994). UVR is a complete carcinogen, which both initiates and promotes carcinogenesis.
UVR initiates carcinogenesis by directly damaging DNA (Berton et al.
1997; de Gruijl 1999; Kunisada et al. 2007), which results in the induction of p53
protein (Ziegler et al. 1994; Berton et al. 1997). The p53 protein transactivates
p21 WAF1/CIP1 inducing cell cycle arrest to allow DNA repair. If the damage is not
repaired, p53-dependent apoptosis is triggered to erase the DNA damage. The p53dependent
apoptosis of UV-damaged normal cells (sunburn cells) is prevented due
to p53 mutation. Thus, these mutated cells can clonally expand to form SCC after
subsequent UVR exposures. In this context, it is notable that mice deficient in p53
have reduced sunburn cell formation and increased susceptibility to UVR-induced
skin carcinogenesis (Li et al. 1998). These findings indicate that apoptosis inhibition
may be an important component of the mechanism of UVR-induced skin
carcinogenesis.
The Fas pathway is important in eliminating DNA-damaged cells both by augmenting
p53-mediated apoptosis (Muller et al. 1998) and by inducing apoptosis
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