OVEREXPRESSION OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P21(WAF1 CIP1) IN HUMAN CUTANEOUS MALIGNANT-MELANOMA/

p21(WAFI/CIPI) (p21) is an inhibitor of cyclin-dependent kinases recen tly identified as the downstream effector of wild-type p53-mediated ce ll cycle arrest. The gene coding for p21 may function as a negative re gulator of melanoma growth, progression, and metastasis. Using immunoh istochemistry and Western blotting, we investigated the expression of p21 in human melanocytic proliferations. Immunohistochemical staining was performed on 13 common acquired nevi, 12 dysplastic nevi, 23 prima ry malignant melanomas, and 12 metastatic melanomas. Common acquired n evi showed minimal p21 staining (1.8+/-0.3%, mean+/-SEM). The percenta ge of positive nuclei was slightly elevated in dysplastic nevi (8.9+/- 1.7%). Both primary malignant melanoma (29+/-3%) and metastatic melano ma (33+/-5%) demonstrated a significantly increased number of p21-posi tive nuclei compared to benign lesions (p<0.001). p21 was strongly exp ressed even in actively proliferating lesions as confirmed by MIB-1 la belling, and although the majority of p21-positive cells likely repres ent a non-proliferating population, staining was occasionally observed in cells undergoing mitosis, suggesting abnormal function of this cel l cycle inhibitor in malignant melanoma. Overexpression of p21 in meta static melanoma compared to common acquired nevi was confirmed by West ern blot analysis of human tumor samples. These findings suggest that increased p21 expression relative to benign nevi is not sufficient to control melanoma growth in vivo.