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10.1038/cddis.2015.67

http://scihub22266oqcxt.onion/10.1038/cddis.2015.67
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suck abstract from ncbi


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pmid25789975
      Cell+Death+Dis 2015 ; 6 (3 ): e1700
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  • Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53-dependent apoptosis in keratinocytes #MMPMID25789975
  • Hall JR ; Messenger ZJ ; Tam HW ; Phillips SL ; Recio L ; Smart RC
  • Cell Death Dis 2015[Mar]; 6 (3 ): e1700 PMID25789975 show ga
  • LincRNA-p21 is a long noncoding RNA and a transcriptional target of p53 and HIF-1?. 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.
  • |Animals [MESH]
  • |Apoptosis/*genetics/radiation effects [MESH]
  • |Cell Cycle Checkpoints/genetics/radiation effects [MESH]
  • |Cell Line [MESH]
  • |Cell Proliferation/genetics/radiation effects [MESH]
  • |DNA Damage/genetics/radiation effects [MESH]
  • |Gene Expression Regulation/radiation effects [MESH]
  • |Humans [MESH]
  • |Keratinocytes/metabolism/pathology/radiation effects [MESH]
  • |Mice [MESH]
  • |RNA, Long Noncoding/*biosynthesis/genetics [MESH]
  • |Skin Neoplasms/*genetics/pathology [MESH]
  • |Skin/metabolism/pathology/radiation effects [MESH]
  • |Tumor Suppressor Protein p53/*genetics [MESH]


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