This study shows increased staining of activated SFKs in human biopsy specimens of psoriasis and cutaneous neoplasia. These data provide direct evidence for increased activation of SFKs in the pathogenesis of hyperproliferative epidermal disorders.

Curcuminoids exhibit anti-proliferative properties in many cell lines by modulating signaling pathways to inhibit cell growth. However, the specific effects of curcuminoids on human keratinocytes are not well defined, and this situation impairs mechanistic thinking regarding potential therapeutic uses. We hypothesized that curcuminoids would modulate key growth regulatory pathways in keratinocytes to inhibit cell proliferation. To test this hypothesis, the effects of curcumin and tetrahydrocurcumin (THC) on MAP kinase signaling in keratinoctyes were determined. Primary human keratinocytes treated with curcumin or THC demonstrated decreased activation of p44/42 MAP kinases but increased levels of activated p38 MAP kinases. These data suggest that curcuminoids specifically activate stress-induced MAP kinases while inhibiting mitogen-induced MAP kinases. Curcuminoids also promote the phosphorylation of p53 on serine 15 in a dose-dependent and p38-dependent manner, suggesting that these compounds may activate p53. The effects of curcuminoids on keratinocytes mirrored some aspects of UVB and could be inhibited by N-acetylcysteine, suggesting that these compounds activate p38 through a mechanism that involves glutathione depletion. Both curcuminoids induced G2/M block and inhibited keratinocyte growth, and THC increased cellular levels of p21, a known p53 transcriptional target. These data demonstrate that curcuminoids can differentially regulate MAP kinases to inhibit keratinocyte growth while inducing p21. Curcuminoids also synergize with UVB to enhance p53 phosphorylation. The findings provide a rationale for testing curcuminoids in disorders associated with impaired p53 function or in which UVB-treatment is efficacious.

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Malignant granular cell tumors are extremely rare, aggressive neoplasms displaying rapid growth and frequent associated metastatic disease. Excision and evaluation for metastatic disease are mandatory. We present a 54-year-old patient with a malignant granular cell tumor, treated with Mohs micrographic surgery. Cutaneous granular cell tumors are uncommon neoplasms, likely of perineural origin. Most follow a benign and uneventful course, with wide local excision being the treatment of choice (Enzinger, 1988). The malignant granular cell tumor is an extremely rare, aggressive variant, which provides a diagnostic challenge and management dilemma, especially with early presentation when it may be mistaken for other entities. There is also controversy regarding surgical management and follow-up of both benign and malignant granular cell tumors.

Background Src-family tyrosine kinases (SFKs) are signaling proteins that regulate keratinocyte proliferation and differentiation. Srcasm is a recently identified molecule that downregulates SFK activity and promotes keratinocyte differentiation. To determine if Srcasm expression correlates with keratinocyte differentiation, we characterized the level of Srcasm expression in some cutaneous lesions that exhibit increased keratinocyte proliferation. Methods Formalin-fixed sections of randomly selected seborrheic keratoses and basal cell carcinomas were analyzed for Srcasm and Ki-67 immunohistochemical staining. Anti-Srcasm and anti- Ki-67 staining were performed in parallel. Results All seborrheic keratoses displayed decreased Srcasm staining in areas comprised of basaloid keratinocytes that exhibited an increased Ki-67 index. Higher Srcasm staining levels were detected near pseudo-horn cysts where keratinocytes exhibited a lower Ki-67 index. All multicentric and nodular basal cell carcinomas displayed a prominent loss of Srcasm staining in association with a marked increase in Ki-67 staining. Conclusions Our results support the hypothesis that Srcasm protein levels are decreased in the hyperproliferative keratinocytes found in seborrheic keratoses and basal cell carcinomas. Increased Srcasm protein levels are detected in keratinocytes undergoing differentiation. Decreased Srcasm levels may be part of the pathophysiologic mechanism in cutaneous lesions exhibiting keratinocyte hyperproliferation.