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.
Subject(s)
Apoptosis/genetics , RNA, Long Noncoding/biosynthesis , Skin Neoplasms/genetics , Tumor Suppressor Protein p53/genetics , Animals , 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/genetics , Skin/metabolism , Skin/pathology , Skin/radiation effects , Skin Neoplasms/pathology , Ultraviolet RaysABSTRACT
The equations governing weakly nonlinear modulations of N-dimensional lattices are considered using a quasidiscrete multiple-scale approach. It is found that the evolution of a short wave packet for a lattice system with cubic and quartic interatomic potentials is governed by the generalized Davey-Stewartson (GDS) equations, which include mean motion induced by the oscillatory wave packet through cubic interatomic interaction. The GDS equations derived here are more general than those known in the theory of water waves because of the anisotropy inherent in lattices. The generalized Kadomtsev-Petviashvili equations describing the evolution of long-wavelength acoustic modes in two- and three-dimensional lattices are also presented. Then the modulational instability of an N-dimensional Stokes lattice wave is discussed based on the N-dimensional GDS equations obtained. Finally, the one- and two-soliton solutions of two-dimensional GDS equations are provided by means of Hirota's bilinear transformation method.
