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.
Highlights
A handful of long noncoding RNAs (ncRNAs) (lncRNAs) have been studied to date and mostly in cell culture
In sun-exposed areas of the human skin, p53 plays an important role in skin cancer prevention through its regulation of keratinocyte cell cycle arrest and apoptosis in response to UVB radiation-induced DNA damage.[17,19,20,21,22,23,24,40]
We have identified lincRNA-p21 as the key mediator of UVB-induced apoptosis in human and mouse keratinocytes
Summary
A handful of lncRNAs have been studied to date and mostly in cell culture These lncRNAs are involved in regulating gene expression through a variety of mechanisms including epigenetic silencing, transcriptional regulation, RNA processing, RNA modification and translation.[4,9] Emerging evidence indicates that lncRNAs are associated with human diseases such as cancer,[10,11] Alzheimer’s12 and heart disease.[13] In lung, liver, prostate and breast cancer, the expression of certain lncRNAs correlates with tumor development, progression or survival.[10,11] Half of all the trait-associated SNPs identified in GWAS are located in noncoding DNA intergenic sequences, and many of the intergenic regions may function by encoding lncRNAs.[14] These results point to important roles of lncRNAs in human disease. Our results reveal that lincRNA-p21 is highly inducible by UVB through a p53dependent mechanism and that lincRNA-p21 has a key role in triggering UVB-induced apoptosis in human and mouse keratinocytes
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