Hall J R, Messenger Z J, Tam H W, Phillips S L, Recio L, Smart R C
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.
1] Department of Biological Sciences, North Carolina State University, Raleigh, NC, USA [2] Toxicology Program, North Carolina State University, Raleigh, NC, USA.
Cell Death Dis. 2015 Mar 19;6(3):e1700. doi: 10.1038/cddis.2015.67.
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.
LincRNA-p21是一种长链非编码RNA，是p53和HIF-1α的转录靶点。LincRNA-p21在顺式和反式作用中调节基因表达、mRNA翻译、蛋白质稳定性、瓦伯格效应以及阿霉素处理的小鼠胚胎成纤维细胞中p53依赖性凋亡和细胞周期停滞。p53通过诱导细胞周期停滞和凋亡，在皮肤角质形成细胞对UVB诱导的DNA损伤的反应中起关键作用。在皮肤癌发生过程中，UVB诱导的p53突变使角质形成细胞在连续暴露于UVB后能够逃避凋亡和细胞周期停滞。我们假设lincRNA-p21在角质形成细胞的UVB诱导凋亡和/或细胞周期停滞中起关键功能作用，而lincRNA-p21功能丧失导致凋亡和/或细胞周期停滞的逃避。我们观察到，在培养的小鼠和人类角质形成细胞以及体内小鼠皮肤中，lincRNA-p21转录本可被UVB高度诱导。LincRNA-p21在转录水平上受UVB调节，角质形成细胞和小鼠表皮体内lincRNA-p21的UVB诱导主要通过p53依赖性途径。敲低lincRNA-p21可阻断UVB诱导的小鼠和人类角质形成细胞凋亡，lincRNA-p21在角质形成细胞中对大部分UVB诱导和p53介导的凋亡负责。敲低lincRNA-p21对未处理或UVB处理的角质形成细胞的细胞增殖没有影响。皮肤癌的早期事件是单个p53等位基因突变。我们观察到，在小鼠表皮（K5Cre(+/tg);LSLp53(+/R172H)）中表达的突变型p53(+/R172H)等位基因对UVB诱导的表皮lincRNA-p21转录和凋亡具有显著的显性负抑制作用。我们得出结论，lincRNA-p21可被UVB高度诱导，在触发UVB诱导的凋亡死亡中起关键作用。我们提出，单个p53等位基因突变通过对UVB诱导的lincRNA-p21表达的显性抑制作用以及随后对UVB诱导凋亡的逃避，在皮肤癌发生早期提供了促癌功能。
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