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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.