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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53-dependent apoptosis in keratinocytes.

Authors: Hall, J R; Messenger, Z J; Tam, H W; Phillips, S L; Recio, L; Smart, R C

Published In Cell Death Dis, (2015 Mar 19)

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.

PubMed ID: 25789975 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis/genetics*; Apoptosis/radiation effects; Cell Cycle Checkpoints/genetics; Cell Cycle Checkpoints/radiation effects; Cell Line; Cell Proliferation/genetics; Cell Proliferation/radiation effects; DNA Damage/genetics; DNA Damage/radiation effects; Gene Expression Regulation/radiation effects; Humans; Keratinocytes/metabolism; Keratinocytes/pathology; Keratinocytes/radiation effects; Mice; RNA, Long Noncoding/biosynthesis*; RNA, Long Noncoding/genetics; Skin Neoplasms/genetics*; Skin Neoplasms/pathology; Skin/metabolism; Skin/pathology; Skin/radiation effects; Tumor Suppressor Protein p53/genetics*; Ultraviolet Rays

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