title: Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53-dependent apoptosis in keratinocytes.
abstract: LincRNA-p21 is a long noncoding RNA and a transcriptional target of p53 and HIF-1α. LincRNA-p21 regulates gene expression in cis and trans, mRNA translation, protein stability, the Warburg effect, and p53-dependent apoptosis and cell cycle arrest in doxorubicin-treated mouse embryo fibroblasts. p53 plays a key role in the response of skin keratinocytes to UVB-induced DNA damage by inducing cell cycle arrest and apoptosis. In skin cancer development, UVB-induced mutation of p53 allows keratinocytes upon successive UVB exposures to evade apoptosis and cell cycle arrest. We hypothesized that lincRNA-p21 has a key functional role in UVB-induced apoptosis and/or cell cycle arrest in keratinocytes and loss of lincRNA-p21 function results in the evasion of apoptosis and/or cell cycle arrest. We observed that lincRNA-p21 transcripts are highly inducible by UVB in mouse and human keratinocytes in culture and in mouse skin in vivo. LincRNA-p21 is regulated at the transcriptional level in response to UVB, and the UVB induction of lincRNA-p21 in keratinocytes and in vivo in mouse epidermis is primarily through a p53-dependent pathway. Knockdown of lincRNA-p21 blocked UVB-induced apoptosis in mouse and human keratinocytes, and lincRNA-p21 was responsible for the majority of UVB-induced and p53-mediated apoptosis in keratinocytes. Knockdown of lincRNA-p21 had no effect on cell proliferation in untreated or UVB-treated keratinocytes. An early event in skin cancer is the mutation of a single p53 allele. We observed that a mutant p53(+/R172H) allele expressed in mouse epidermis (K5Cre(+/tg);LSLp53(+/R172H)) showed a significant dominant-negative inhibitory effect on UVB-induced lincRNA-p21 transcription and apoptosis in epidermis. We conclude lincRNA-p21 is highly inducible by UVB and has a key role in triggering UVB-induced apoptotic death. We propose that the mutation of a single p53 allele provides a pro-oncogenic function early in skin cancer development through a dominant inhibitory effect on UVB-induced lincRNA-p21 expression and the subsequent evasion of UVB-induced apoptosis.
authors: 1] Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA [2] Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA [3] Toxicology Program, North Carolina State University, Raleigh, NC, USA.
authors: J R
authors: JR
authors: Hall
authors: 1] Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA [2] Toxicology Program, North Carolina State University, Raleigh, NC, USA.
authors: Z J
authors: ZJ
authors: Messenger
authors: 1] Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA [2] Toxicology Program, North Carolina State University, Raleigh, NC, USA.
authors: H W
authors: HW
authors: Tam
authors: ILS, Research Triangle Park, NC, USA.
authors: S L
authors: SL
authors: Phillips
authors: ILS, Research Triangle Park, NC, USA.
authors: L
authors: L
authors: Recio
authors: 1] Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA [2] Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA [3] Toxicology Program, North Carolina State University, Raleigh, NC, USA.
authors: R C
authors: RC
authors: Smart
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000528:radiation effects; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014466:Ultraviolet Rays
chemical_list: D062085:RNA, Long Noncoding; D016159:Tumor Suppressor Protein p53