title: p21 cooperates with DDB2 protein in suppression of ultraviolet ray-induced skin malignancies.
abstract: Exposure to ultraviolet rays (UV) in sunlight is the main cause of skin cancer. Here, we show that the p53-induced genes DDB2 and p21 are down-regulated in skin cancer, and in the mouse model they functionally cooperate to prevent UV-induced skin cancer. Our previous studies demonstrated an antagonistic role of DDB2 and p21 in nucleotide excision repair and apoptosis. Surprisingly, we find that the loss of p21 restores nucleotide excision repair and apoptosis in Ddb2(-/-) mice, but it does not protect from UV-mediated skin carcinogenesis. In contrast, Ddb2(-/-)p21(-/-) mice are significantly more susceptible to UV-induced skin cancer than the Ddb2(-/-) or the p21(-/-) mice. We provide evidence that p21 deletion in the Ddb2(-/-) background causes a strong increase in cell proliferation. The increased proliferation in the Ddb2(-/-)p21(-/-) background is related to a severe deficiency in UV-induced premature senescence. Also, the oncogenic pro-proliferation transcription factor FOXM1 is overexpressed in the p21(-/-) background. Our results show that the anti-proliferative and the pro-senescence pathways of DDB2 and p21 are critical protection mechanisms against skin malignancies.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Cancer Center, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Stoyanova
authors.forename: Nilotpal
authors.initials: N
authors.lastname: Roy
authors.forename: Shaumick
authors.initials: S
authors.lastname: Bhattacharjee
authors.forename: Dragana
authors.initials: D
authors.lastname: Kopanja
authors.forename: Ted
authors.initials: T
authors.lastname: Valli
authors.forename: Srilata
authors.initials: S
authors.lastname: Bagchi
authors.forename: Pradip
authors.initials: P
authors.lastname: Raychaudhuri
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000528:radiation effects; D016922:Cellular Senescence / Q000235:genetics / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects; D004268:DNA-Binding Proteins; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C496850:Ddb2 protein, mouse; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D016159:Tumor Suppressor Protein p53