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Conserved regions: C,-C,

Variable regions: V,-V, b, e, I, n lack C, region and are calcium-independent protein kinases

Fig. 5. Protein kinase C family.

Tumors

PKCd occupies a central position in a cell's signaling network that regulates a wide variety of cellular processes, which include suppression of cell proliferation and transformation, and induction of apoptosis and differentiation (34). We found PKCd to be a potent suppressor of the induction of both papillomas and carcinomas in intact mouse skin in vivo. The mechanism by w hich PKCd overexpression results in inhibition of skin tumor formation is yet unclear. TPA-induced ODC activity has been shown to be correlated with mouse skin tumor promotion (2 4). Such a correlation was not observed in PKCd transgenic mice. On the contrary, PKCd overexpression suppressed TPA-induced tumor formation, whereas it superinduced ODC activity, indicating that PKC d-mediated signals to ODC induction and skin tumor suppression are not on the same linear pathway. TPA-induced ODC gene expression appears to be mediated by PKCd activation. Specific examples are the observations that co-transfection of a PKCd expression vector with an ODC promoter (772/+ 130 ODC-Luc) enhanced the reporter gene activity (41) and inhibition of PKCd activity by use of a dominant-negative PKCd inhibited the induction of ODC activity (42). The transgenic mice, which overexpress PKCd in their epidermis, are more responsive to TPA for the induction of ODC activity than their wild-type littermates. Overinduction of ODC was observed either after a single or repeated TPA application to skin. It is noteworthy that the levels of both epi dermal PKCd protein and PKCd activity remained increased, which correlated with the induction of ODC activity in PKCd transgenic mice. It appears that the PKCd activity level determines the degree of induction of ODC activity by TPA. DFMO, which inhibits TPA-induced ODC activity (43), did not alter the response of PKCd transgenic mice to skin tumor promotion by TPA. If ODC had been downstream of PKCd signals to skin tumor suppression, then inhibition of ODC activity by DFMO treatment could have reversed the tumor susceptibility of PKCd transgenic mice to their wild-type lit-termates. The lack of effect of DFMO treatment on the sensitivity of PKCd transgenic mice to skin tumor promotion by TPA indicates that the PKCd-mediated signals to ODC induction and skin tumor suppression are not on the same linear pathway. The lack of correlation between TPA-induced ODC activity and skin tumor multiplicity in PKC d transgenic mice can be explained as follows: ODC is the key enzyme in the biosynthesis of mammalian polyamines, which regulate a wide variety of cellular processes. The level of polyamines is regulated at the levels of biosynthesis, interconversion, and degradation (44,45). Polyamines spermidine and spermine are acetylated and then excreted to maintain the intracellular polyamine pool. Although ODC is superinduced in PKCd transgenic mice, it is likely that because of interconversion, degradation, and excretion that a critical level of polyamines or spermidine/spermine ratio essential to favor tumor promotion is never achieved. PKCd may activate a signaling pathway, independent of one leading to ODC induction, which may interfere with polyamine specific signals to skin tumor promotion by TPA (46).

3.3. PKCe Activation Linked to ODC Induction and SCC

The role of TPA-stimulated polyamine biosynthesis in the development of metasta-tic squamous cell carcinoma (mSCC) in PKCe transgenic mice was determined. TPA treatment induced epidermal ODC activity and putrescine levels approx three- to fourfold more in PKCe transgenic mice than their wild-type littermates. Development of mSCC by the 7,12-dimethylbenz(a)anthracene (100 nmol)-TPA (5 nmol) protocol in PKCe transgenic mice was completely prevented by administration of the suicide inhibitor of ODC-DFMO (0.5% w/v) in the drinking water during TPA pro motio n. However, DFMO treatment led to marked hair loss in PKCe transgenic mice. DFMO treatment-associated hair loss in PKCe transgenic mice was accompanied by a decrease in the number of intact hair follicles. These results indicate that TPA-induced ODC activity and the resultant accumulation of putrescine in PKCe transgenic mice are linked to growth and maintenance of hair follicles and the development of mSCC (47).

When the FVB/N wild-type mice were given 0.5% DFMO in their drinking water during tumor promotion, little effect in hair loss was noted. However, PKCe transgenic mice exhibited severe hair loss, which on histological examination revealed almost complete loss of hair follicles. These results indicate that PKCe and ODC may play, in concert, pivotal roles in the development, growth, and maintenance of the hair follicle. ODC expression has been linked to hair follicle cycling. ODC is abundantly expressed in the lower part of the follicular bulb in the anagen (growth phase) of the hair cycle, whereas no expression is detected in either the catagen (regression phase) or telogen

Fig. 6. Protein kinase Ce overexpression sensitizes skin through the induction of squamous cell carcinoma, either by the DMBA-TPA proto-or repeated ultraviolet radiation exposure.

(resting phase) phases of the hair cycle. As compared with the wild-type littermates, PKC transgenic mice exhibited hyperplasia of the hair follicle during skin tumor promotion by TPA. DFMO treatment, in conjunction with TPA promotion, led to almost complete loss of the hair follicle with an extreme thickening of the interfollicular epidermis in PKCe transgenic mice. The target cells for skin papillomas and carcinomas have been postulated previously either to be the basal keratinocytes of the interfollicular epidermis or the cells that form the outer root sheath of the hair follicle. The results presented here additionally strengthen our findings that the carcinomas in PKCe trans-genic mice originate from cells in the hair follicle (47).

3.3.1. TNF-a Linked to PKCe-Mediated Development of SCC

We found that PKCe transgenic mice elicit elevated serum TNF-a levels during skin tumor promotion by TPA, and this increase may be linked to the development of mSCC. A single topical application of TPA (5 nmol) to the skin, as early as 2.5 h after treatment, resulted in a significant (p < 0.01) increase (twofold) in epidermal TNF-a, and more than a sixfold increase in ectodomain shedding of TNF - a into the serum of PKCe t ra ns-genic mice relative to their wild-type littermates. Furthermore, this TPA-stimulated TNF-a shedding was proportional to the level of expression of PKCe in the epidermis. Using the TNF-a-converting enzyme (TACE) inhibitor, TAPI-1, TPA-stimulated TNF-a shedding could be completely prevented in PKCe transgenic mice and isolated ker-atinocytes. These results indicate that PKCe signal transduction pathways to TPA-stimulated TNF - a ectodomain shedding are mediated by TACE, a transmembrane metalloprotease. Using the superoxide dismutase mimetic CuDIPs and the glutathione reductase mimetic ebselen, TPA-stimulated TNF-a shedding from PKCe trans ge nic mice could be completely attenuated, implying the role of reactive oxygen species. Finally, ip injection of a TNF-a synthesis inhibitor, pentoxifylline, during skin tumor promotion completely prevented the development of mSCC in PKCe transgenic mice. Taken together, these results indicate that: PKCe activation is an initial signal in TPA-induced shedding of TNF-a from epidermal keratinocytes; PKCe-mediated signals to TACE are possibly mediated through reactive oxygen species; and T PA-induced TNF-a shedding may play a role in the development of mSCC in PKCe transgenic mice (48).

The role of TNF-a in UVR-induced cutaneous damage was also evaluated using PKCe transgenic mice deficient in TNF-a (13). UVR treatment, three times weekly for 13 wk at 2 kJ/m2, induced severe cutaneous damage in PKCe transgenic mice (line 215), which was prevented in PKCe transgenic-TNF-a knockout mice. Taken together, the results indicate that PKCe signals UVR-induced TNF - a release that is linked, at least in part, to the photosensitivity of PKCe transgenic mice.

PKCe transgenic mice were also observed to be more sensitive than their wild-type littermates to UVR-induced release of cytokines (interleukin [IL]-5, IL-6, IL-10; gran-ulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor) other than TNF-a. It is likely that there is crosstalk among cytokines. It is notable that TNF-a has been shown to regulate the production of several cytokines.

TNF-a signal transduction pathways in UVR-induced cutaneous damage and development of SCC are not known. TNF-a mediates the activation of two transcriptional

Flavonoids (quercetin, genistein, apigenin )

Carotenoids: (lycopene, neoxanthin

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