Translational control of a human <i>CDKN1A</i> mRNA splice variant regulates the fate of UVB-irradiated human keratinocytes

Collier, Ann E.; Spandau, Dan F.; Wek, Ronald C.

doi:10.1091/mbc.e17-06-0362

Cited by 20 publications

(18 citation statements)

References 66 publications

(96 reference statements)

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“…It remains unexplored the possibility that the different transcript variants are preferentially associated with one or other cell fate. Additionally, translational regulation at the 5’ UTR of the variants has been shown to affect cell fate [ 11 , 21 ]. Human cells also express several Cdkn1a transcript variants [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Human cells also express several Cdkn1a transcript variants [ 22 ]. Among the ten human transcript variants currently annotated, at least one (transcript variant 4) shares translational regulatory mechanisms with the murine p21var2 [ 21 ]. Interestingly, even though murine variant 2 and human variant 4 do not appear to share sequence homology, the translational regulation in both transcripts is driven by the integrated stress response and results in cell cycle arrest [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…Among the ten human transcript variants currently annotated, at least one (transcript variant 4) shares translational regulatory mechanisms with the murine p21var2 [ 21 ]. Interestingly, even though murine variant 2 and human variant 4 do not appear to share sequence homology, the translational regulation in both transcripts is driven by the integrated stress response and results in cell cycle arrest [ 21 ]. The potential relevance of this mechanism for cellular senescence in humans remains unknown, and the functions and interrelations of the different Cdkn1a transcript variants have not been studied in depth.…”

Section: Discussionmentioning

confidence: 99%

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Cdkn1a transcript variant 2 is a marker of aging and cellular senescence

López-Domínguez

Rodríguez-López

Ahumada-Castro

et al. 2021

Aging

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Cellular senescence is a cell fate response characterized by a permanent cell cycle arrest driven primarily the by cell cycle inhibitor and tumor suppressor proteins p16 Ink4a and p21 Cip1/Waf1 . In mice, the p21 Cip1/Waf1 encoding locus, Cdkn1a , is known to generate two transcripts that produce identical proteins, but one of these transcript variants is poorly characterized. We show that the Cdkn1a transcript variant 2, but not the better-studied variant 1, is selectively elevated during natural aging across multiple mouse tissues. Importantly, mouse cells induced to senescence in culture by genotoxic stress (ionizing radiation or doxorubicin) upregulated both transcripts, but with different temporal dynamics: variant 1 responded nearly immediately to genotoxic stress, whereas variant 2 increased much more slowly as cells acquired senescent characteristics. Upon treating mice systemically with doxorubicin, which induces widespread cellular senescence in vivo , variant 2 increased to a larger extent than variant 1. Variant 2 levels were also more sensitive to the senolytic drug ABT-263 in naturally aged mice. Thus, variant 2 is a novel and more sensitive marker than variant 1 or total p21 Cip1/Waf1 protein for assessing the senescent cell burden and clearance in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cdkn1a transcript variant 2 is a marker of aging and cellular senescence

López-Domínguez

Rodríguez-López

Ahumada-Castro

et al. 2021

Aging

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“…4A , Supplementary Table 1 ). Upregulation of CDKN1A by UVB is tightly controlled by MDM2 and p53 [ 45 , 46 ]. CDKN1A regulates cell cycle progression at G1 by inhibiting cyclin-CDK2 or -CDK4 complexes, regulates DNA repair in S-phase by interacting with proliferating cell nuclear antigen (PCNA), and has p53 independent effects on cell cycle and apoptosis [ 47 ] ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Therapeutic wavelengths of ultraviolet B radiation activate apoptotic, circadian rhythm, redox signalling and key canonical pathways in psoriatic epidermis

et al. 2021

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Ultraviolet B radiation (UVB) exerts pleiotropic effects on human skin. DNA damage response and repair pathways are activated by UVB; if damage cannot be repaired, apoptosis ensues. Although cumulative UVB exposure predisposes to skin cancer, UVB phototherapy is widely used as an effective treatment for psoriasis. Previous studies defined the therapeutic action spectrum of UVB and showed that psoriasis is resistant to apoptosis. This study aimed to investigate early molecular responses within psoriasis plaques following irradiation with single equi-erythemogenic doses of clinically-effective (311 nm, narrow-band) compared to clinically-ineffective (290 nm) UVB. Forty-eight micro-dissected epidermal samples from 20 psoriatic patients were analyzed using microarrays. Our bioinformatic analysis compared gene expression between 311 nm irradiated, 290 nm irradiated and control psoriasis epidermis to specifically identify 311 nm UVB differentially expressed genes (DEGs) and their upstream regulatory pathways. Key DEGs and pathways were validated by immunohistochemical analysis. There was a dynamic induction and repression of 311 nm UVB DEGs between 6 h and 18 h, only a limited number of DEGs maintained their designated expression status between time-points. Key disease and function pathways included apoptosis, cell death, cell migration and leucocyte chemotaxis. DNA damage response pathways, NRF2-mediated oxidative stress response and P53 signalling were key nodes, interconnecting apoptosis and cell cycle arrest. Interferon signalling, dendritic cell maturation, granulocyte adhesion and atherosclerotic pathways were also differentially regulated. Consistent with these findings, top transcriptional regulators of 311 nm UVB DEGs related to: a) apoptosis, DNA damage response and cell cycle control; b) innate/acquired immune regulation and inflammation; c) hypoxia/redox response and angiogenesis; d) circadian rhythmicity; f) EGR/AP1 signalling and keratinocyte differentiation; and g) mitochondrial biogenesis. This research provides important insights into the molecular targets of 311 nm UVB, underscoring key roles for apoptosis and cell death. These and the other key pathways delineated may be central to the therapeutic effects of 311 nm in psoriasis.

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“…41 In a recent report, Collier et al indicated that when cells in response to sublethal ultraviolet B radiation, genome-wide analysis reveals preferential translation of a series of genes undergoing AS events following radiation, of which the CDKN1A splice variants regulated the fate of radiation-insulted human keratinocytes. 42 Other environmental stresses, such as hypoxia, have been also found to induce the occurrence of alternative events. As stated in the study reported by Bowler et al, hypoxia leads to significant changes in AS in prostate cancer cells and the CLK splice factor kinase could be targeted in cancers in which hypoxia contributes to cancer therapy resistance.…”

Section: Discussionmentioning

confidence: 99%

PRKCSH Alternative Splicing Involves in Silica-Induced Expression of Epithelial–Mesenchymal Transition Markers and Cell Proliferation

Huang

Liu

et al. 2020

Dose-Response

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Background: Mounting evidence suggests that alternative splicing is one of the ways for cells to adapt to environmental stress insults. The aim of this study was firstly to examine the effect of silica on the alternative splicing of lung fibrosis–associated genes. Methods: Microarray analysis was used to construct the alternative splicing profile. Functional experiments were conducted using Cell Counting Kit-8, cell cycle, apoptosis, and epithelial–mesenchymal transition (EMT) analyses. Alternative splicing variants were verified by quantitative real-time polymerase chain reaction (qRT-PCR) polymerase chain reaction method. Results: A total of 1850 genes that have alternative splices in response to silica insult were identified. PCDHB11, MALAT1, MT2A, RP11-126D17.1, and RP11-415I12.2 are the top 5 upregulated genes with occurrence of alternative splice, whereas NDE1, RNPEPL1, TREML2, CSF2RB, and PRKCSH are the top 5 downregulated genes with occurrence of alternative splice. Bioinformatic analysis showed these genes with the occurrence of alternative splice mainly are associated with EMT pathway, N-Glycan biosynthesis, and leukocyte transendothelial migration. Further study indicated that PRKCSH-2 knockdown promotes A549 cell proliferation potential by partially promoting EMT signals. Conclusions: Significant changes in alternative splicing of silicosis-associated genes occur in patients with silicosis in silica conditions. Our study provides basic founding for further investigation into the detail molecular mechanisms underlying silica-induced silicosis.

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Translational control of a human CDKN1A mRNA splice variant regulates the fate of UVB-irradiated human keratinocytes

Abstract: Phosphorylation of eIF2 and the integrated stress response in response to UVB are cytoprotective by a mechanism featuring preferential translation of a specific splice variant of CDKN1A that facilitates G1 arrest and subsequent DNA repair.

Cited by 20 publications

References 66 publications

Cdkn1a transcript variant 2 is a marker of aging and cellular senescence

Cdkn1a transcript variant 2 is a marker of aging and cellular senescence

Therapeutic wavelengths of ultraviolet B radiation activate apoptotic, circadian rhythm, redox signalling and key canonical pathways in psoriatic epidermis

PRKCSH Alternative Splicing Involves in Silica-Induced Expression of Epithelial–Mesenchymal Transition Markers and Cell Proliferation

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