The major findings of our study are: (i) HO-1-deficient mice are more vulnerable to DMBA/PMA-induced skin injury, (ii) lack of HO-1 results in the development of large, but benign, papillomas in response to DMBA/PMA treatment, whereas HO-1 expression seems to facilitate a transformation of growing tumors to malignant carcinoma; and (iii) HO-1-deficient fibroblasts exposed to DMBA demonstrate more pronounced upregulation of p21, cyclin-D1, and cyclin-D2 expression, but are less susceptible to c-myc-mediated transformation. The gene discussed is CCND2; the disease is papilloma.