The atypical protein kinase C (aPKC)-partition-defective (PAR) complex regulates the formation of tight junctions and apico-basal epithelial polarity. To examine the role of this complex in the epidermis, we generated mutant mice harboring epidermal-specific deletion of aPKCλ (conditional knock-out (cKO)), a major component of the aPKC-PAR complex. The mutant mice exhibited abnormal hair follicle (HF) cycling, progressive losses of pelage hairs and vibrissae, and altered differentiation into the epidermis and sebaceous gland. We found that in the aPKCλ cKO mice HF stem cell (HFSC) quiescence was lost, as revealed by the decreased expression level of quiescence-inducing factors (Fgf18 and Bmp6) produced in Keratin 6-positive bulge stem cells. The loss of quiescence dysregulated the HFSC marker expression and led to the increase in Lrig1-positive cells, inducing hyperplasia of the interfollicular epidermis and sebaceous glands, and drove an increase in Lef1-positive matrix cells, causing a prolonged anagen-like phase. Persistent bulge stem cell activation led to a gradual depletion of CD34- and α6 integrin-positive HFSC reservoirs. These results suggest that aPKCλ regulates signaling pathways implicated in HFSC quiescence.

BackgroundThe clinical course of human papillomavirus (HPV) associated with Bowenoid papulosis and condyloma acuminatum of anogenital tumors are still unknown. Here we evaluated molecules that are relevant to cellular proliferation and regulation of apoptosis in HPV associated anogenital tumors.MethodsWe investigated the levels of telomerase activity, and inhibitor of apoptosis proteins (IAPs) family (c-IAP1, c-IAP2, XIAP) and c-Myc mRNA expression levels in 20 specimens of Bowenoid papulosis and 36 specimens of condyloma acuminatum in anogenital areas. Overall, phosphorylated (p-) AKT, p-ribosomal protein S6 (S6) and p-4E-binding protein 1 (4EBP1) expression levels were examined by immunohistochemistry in anogenital tumors both with and without positive telomerase activity.ResultsPositive telomerase activity was detected in 41.7% of Bowenoid papulosis and 27.3% of condyloma acuminatum compared to normal skin (p < 0.001). In contrast, the expression levels of Bowenoid papulosis indicated that c-IAP1, c-IAP2 and XIAP mRNA were significantly upregulated compared to those in both condyloma acuminatum samples (p < 0.001, p < 0.001, p = 0.022, respectively) and normal skin (p < 0.001, p = 0.002, p = 0.034, respectively). Overall, 30% of Bowenoid papulosis with high risk HPV strongly promoted IAPs family and c-Myc but condyloma acuminatum did not significantly activate those genes. Immunohistochemically, p-Akt and p-S6 expressions were associated with positive telomerase activity but not with p-4EBP1 expression.ConclusionCombined analysis of the IAPs family, c-Myc mRNA expression, telomerase activity levels and p-Akt/p-S6 expressions may provide clinically relevant molecular markers in HPV associated anogenital tumors.

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