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9 Molecular Biology of Vitamin D Metabolism and Skin Cancer 207

phosphorylation with control HPK1A cells was detected with over expression of
active MAPK kinase and these cells failed to drive reporter activity. The reverse
was then tested by using the 1,25(OH) D resistant HPK1A Ras cells expressing a
2 3
mutant RXR of serine to alanine at the relevant position. Indeed the restoration of
reporter activity and the detection of serine phosphorylation confirmed that an acti-
vated Ras/MAPK signaling pathway in tumor cells can cause the phosphorylation
of the RXR, which in turn may interfere with 1,25(OH) D transactivation mediated
2 3
growth inhibition. Further understanding of the exact mechanism of how RXR
phosphorylation can lead to the disturbance of its interaction with proteins required
for 1,25(OH) D transactivation, which could yield important ideas for chemopre-
2 3
vention therapies.

9.5.4 The Role of Vitamin D in Photoprotection

The most well known consequence of UVB radiation is the appearance of apop-
totic or sunburn cells [88]. Cellular stresses including UV irradiation activates
c-Jun NH2-terminal kinase (JNK) [74] and there is evidence that upregulation of
stress activated protein kinases (SAPKs) promotes apoptosis [158, 163]. The
tumor suppressor gene, p53, can either induce cell cycle arrest by upregulating
cyclin dependant kinase inhibitor P21 [144] or inducing apoptosis if the damage
is extensive and cannot be repaired [37]. The interaction between JNK and p53,
and the precise pathway of JNK mediated apoptosis and carcinogenesis is not yet
fully elucidated. The interaction of p53 with JNK could conceivably prevent the
interaction of p53 to the p21 promoter to inhibit cell cycle arrest and thus favors
apoptosis [142]. It has been demonstrated that JNK2 knockout mice have a lower
number of papillomas and malignant tumors induced by 12-O-tetradecanoylphor-
bol-13-acetate compared to wild type mice, suggesting that JNK2 is critical in
tumor promotion [27].
De Haes et al. found that pretreating keratinocytes for 24 h prior to UVB radia-
tion with pharmacological dose of 1,25(OH) D (1 mM) reduced apoptosis by
2 3
55–70%. Moreover, a reduction of UVB stimulated JNK activation of more than
30% was also found together with a 90% inhibition of mitochondrial cytochrome c
release [33]. This can possibly be explained by the recent finding of the ability of
p53 to protect cells against UV induced apoptosis via the binding and inactivation
of JNK pathway, which is responsible for the induction of mitochondrial death
signaling [99].
It has also been noted [33] that the culture conditions in terms of dose and pre-
incubation time of 1,25(OH) D were very similar to those used to conduct growth
2 3
inhibition experiments on proliferating keratinocytes [14, 139]. It is hypothesized
that the observed accumulation of keratinocytes in the G phase of these experi-
1
ments may have protected the DNA from the genotoxic effects of UVB, as the
unfolded structure of DNA in the S phase will render it more susceptible to UVB
induced DNA damage [123]. This hypothesis is in agreement with the findings of