2015 journal article
Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53-dependent apoptosis in keratinocytes
CELL DEATH & DISEASE, 6.
MeSH headings : 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 / metabolism; Skin / pathology; Skin / radiation effects; Skin Neoplasms / genetics; Skin Neoplasms / pathology; Tumor Suppressor Protein p53 / genetics; Ultraviolet Rays
open access via www.nature.com (publisher PDF)
UN Sustainable Development Goal Categories
3. Good Health and Well-being
(Web of Science; OpenAlex)
Source: Web Of Science
Added: August 6, 2018
AbstractLincRNA-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.