Activation of the JNKs/ATM-p53 axis is indispensable for the cytoprotection of dermal fibroblasts exposed to UVB radiation.
Animals
Apoptosis
/ radiation effects
Ataxia Telangiectasia Mutated Proteins
/ metabolism
Cytoprotection
ErbB Receptors
/ metabolism
Fibroblasts
/ metabolism
Humans
Mice
NF-E2-Related Factor 2
/ genetics
Phosphorylation
Proto-Oncogene Proteins c-akt
/ metabolism
Tumor Suppressor Protein p53
/ metabolism
Ultraviolet Rays
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
25 07 2022
25 07 2022
Historique:
received:
03
02
2022
accepted:
14
07
2022
revised:
12
07
2022
entrez:
25
7
2022
pubmed:
26
7
2022
medline:
28
7
2022
Statut:
epublish
Résumé
Although UVB radiation is mainly absorbed by the epidermis, ~5-10% of its photons reach and affect the upper part of the dermis. Physiologically relevant UVB doses, able to provoke erythema, induce apoptosis in human dermal fibroblasts in vitro, as well as in the dermis of SKH-1 mice. Given the sparse and even contradictory existing information on the effect of UVB radiation on dermal fibroblasts' viability, aim of this work was to unravel the crucial signaling pathways regulating the survival of UVB-treated human dermal fibroblasts. We found that UVB radiation immediately stimulates the phosphorylation of MAPK family members, as well as Akt, and is genotoxic leading to the delayed ATM-p53 axis activation. Akt phosphorylation after UVB radiation is EGFR-mediated and EGFR inhibition leads to a further decrease of viability, while the Akt activator SC79 rescues fibroblasts to an extent by a mechanism involving Nrf2 activation. The known Nrf2 activator sulforaphane also exerts a partial protective effect, although by acting in a distinct mechanism from SC79. On the other hand, inhibition of JNKs or of the ATM-p53 axis leads to a complete loss of viability after UVB irradiation. Interestingly, JNKs activation is necessary for p53 phosphorylation, while the ATM-p53 pathway is required for the long-term activation of JNKs and Akt, reassuring the protection from UVB. Although UVB radiation results in intense and prolonged increase of intracellular ROS levels, classical anti-oxidants, such as Trolox, are unable to affect Akt, JNKs, or p53 phosphorylation and to reverse the loss of fibroblasts' viability. Collectively, here we provide evidence that the main viability-regulating UVB-triggered biochemical pathways act synergistically towards the protection of human dermal fibroblasts, with EGFR/Akt and Nrf2 serving as auxiliary anti-apoptotic machineries, while JNKs/ATM-p53 activation and interplay being overriding and indispensable for the perpetuation of cellular defense and the maintenance of cell viability.
Identifiants
pubmed: 35879280
doi: 10.1038/s41419-022-05106-y
pii: 10.1038/s41419-022-05106-y
pmc: PMC9314411
doi:
Substances chimiques
NF-E2-Related Factor 2
0
Tumor Suppressor Protein p53
0
ErbB Receptors
EC 2.7.10.1
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
647Informations de copyright
© 2022. The Author(s).
Références
Cancers (Basel). 2021 Apr 20;13(8):
pubmed: 33924197
PLoS One. 2012;7(12):e50944
pubmed: 23251405
J Biol Chem. 2012 May 18;287(21):17554-17567
pubmed: 22467874
Toxicol Rep. 2017 Aug 01;4:441-449
pubmed: 28959672
J Biol Chem. 2011 Jul 1;286(26):22825-32
pubmed: 21561856
Nat Protoc. 2008;3(7):1125-31
pubmed: 18600217
Biomaterials. 2010 Nov;31(33):8530-8
pubmed: 20708793
Biomed Mater. 2018 Oct 26;14(1):014101
pubmed: 30362459
Photochem Photobiol. 2012 Sep-Oct;88(5):1048-65
pubmed: 22780837
Dev Cell. 2018 Jul 16;46(2):145-161.e10
pubmed: 30016619
Cell Death Dis. 2017 Feb 2;8(2):e2576
pubmed: 28151469
J Invest Dermatol. 2009 Jul;129(7):1805-15
pubmed: 19242509
Oncotarget. 2016 Sep 13;7(37):60123-60132
pubmed: 27517753
J Physiol Sci. 2019 May;69(3):489-502
pubmed: 30771091
Cell Death Dis. 2019 Jan 8;10(1):19
pubmed: 30622245
Rev Environ Health. 2014;29(3):243-54
pubmed: 25241726
Nucleic Acids Res. 2020 Sep 18;48(16):9109-9123
pubmed: 32729622
Oncogene. 2003 Sep 1;22(37):5885-96
pubmed: 12947395
Science. 2000 May 5;288(5467):870-4
pubmed: 10797012
Arch Biochem Biophys. 2010 Sep 1;501(1):142-50
pubmed: 20558128
Oncotarget. 2017 Dec 20;9(16):12639-12648
pubmed: 29560097
Biochim Biophys Acta. 2014 Aug;1840(8):2635-42
pubmed: 24735795
J Invest Dermatol. 2013 Jul 01;133(E1):E2-6
pubmed: 23820721
Free Radic Biol Med. 2019 Sep;141:220-232
pubmed: 31220549
Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10070-5
pubmed: 16006525
Elife. 2021 Dec 23;10:
pubmed: 34939928
J Biol Chem. 2000 Dec 15;275(50):39435-43
pubmed: 10993883
Cell Cycle. 2010 Aug 1;9(15):2917-8
pubmed: 20699662
J Biol Chem. 2000 Feb 11;275(6):4336-44
pubmed: 10660603
Mol Cancer. 2013 Dec 24;12(1):172
pubmed: 24365180
Arch Dermatol Res. 2010 Jan;302(1):5-17
pubmed: 19756672
J Invest Dermatol. 1999 May;112(5):751-6
pubmed: 10233767
J Invest Dermatol. 2010 Apr;130(4):1095-106
pubmed: 20090768
J Invest Dermatol. 2005 Apr;124(4):825-32
pubmed: 15816842
Int J Mol Sci. 2017 Dec 20;18(12):
pubmed: 29261130
Oncotarget. 2017 Feb 28;8(9):14978-14987
pubmed: 28122357
J Invest Dermatol. 2001 Nov;117(5):1234-40
pubmed: 11710938
Photochem Photobiol. 2015 Jan-Feb;91(1):140-55
pubmed: 25327445
Eur Cell Mater. 2015 Sep 04;30:89-102; discussion 103
pubmed: 26337541
J Dermatol Sci. 2016 Feb;81(2):107-17
pubmed: 26674123
Cell Physiol Biochem. 2018;46(5):1849-1860
pubmed: 29705807
Molecules. 2017 Sep 29;22(10):
pubmed: 28961200
Photodermatol Photoimmunol Photomed. 2010 Aug;26(4):198-204
pubmed: 20626822
Matrix Biol Plus. 2021 Feb 20;10:100057
pubmed: 34195594
Cancer Res. 1987 Aug 1;47(15):4229-34
pubmed: 3111682
J Formos Med Assoc. 2007 Nov;106(11):975-8
pubmed: 18063522
Cancer Res. 2008 Apr 1;68(7):2523-9
pubmed: 18381462
Mol Med Rep. 2012 Jan;5(1):54-9
pubmed: 21909619
Food Chem Toxicol. 2008 Apr;46(4):1298-307
pubmed: 18226437
Eur Spine J. 2017 Aug;26(8):2063-2071
pubmed: 28646455
NPJ Breast Cancer. 2020 Jan 3;6:2
pubmed: 31909186
Sci Rep. 2021 May 11;11(1):9963
pubmed: 33976251
Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8493-7
pubmed: 7667317
Oncogene. 2010 Jan 28;29(4):492-502
pubmed: 19881543
Photochem Photobiol. 2004 Jun;79(6):540-4
pubmed: 15291306
Exp Gerontol. 2017 Aug;94:78-82
pubmed: 28093316
Mutat Res. 2005 Apr 1;571(1-2):3-17
pubmed: 15748634
Am J Pathol. 2018 May;188(5):1171-1182
pubmed: 29673487
J Biol Chem. 2005 Dec 30;280(52):43257-63
pubmed: 16278215
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10541-6
pubmed: 9724739
J Investig Dermatol Symp Proc. 1999 Sep;4(1):17-23
pubmed: 10537002
Toxicol Appl Pharmacol. 2004 Mar 15;195(3):288-97
pubmed: 15020191
Arch Dermatol Res. 2010 Mar;302(2):71-83
pubmed: 19898857
Indian J Dermatol Venereol Leprol. 2007 Mar-Apr;73(2):97-9
pubmed: 17456914
Toxicology. 2003 Jul 15;189(1-2):21-39
pubmed: 12821280
Drug Des Devel Ther. 2020 Jan 29;14:417-428
pubmed: 32099326
Clin Exp Dermatol. 2001 Oct;26(7):573-7
pubmed: 11696060
Genes Cancer. 2013 Sep;4(9-10):360-8
pubmed: 24349633
J Cell Physiol. 2012 Mar;227(3):1179-87
pubmed: 21604265
Genes Dev. 2010 May 15;24(10):1045-58
pubmed: 20478997
J Cell Physiol. 2006 Dec;209(3):775-85
pubmed: 16972255
Sci Rep. 2020 Nov 3;10(1):18946
pubmed: 33144600
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
Photochem Photobiol. 2005 Jul-Aug;81(4):975-82
pubmed: 15807633
BMC Dermatol. 2016 May 26;16(1):6
pubmed: 27230291
Toxicol Appl Pharmacol. 2018 Dec 1;360:69-77
pubmed: 30268578
DNA Repair (Amst). 2009 Aug 6;8(8):930-43
pubmed: 19535302
Aging (Albany NY). 2016 Aug;8(8):1650-69
pubmed: 27434331
Mol Carcinog. 2011 Jun;50(6):479-86
pubmed: 21557329
Arch Dermatol Res. 2012 Jul;304(5):407-12
pubmed: 22271212
J Cell Physiol. 1987 Jul;132(1):143-8
pubmed: 3496343
Biochem Biophys Res Commun. 2016 Oct 7;479(1):54-60
pubmed: 27614310
J Orthop Res. 2014 Dec;32(12):1701-7
pubmed: 25220975
Carcinogenesis. 2005 Aug;26(8):1404-13
pubmed: 15831527
FEBS J. 2013 Sep;280(18):4572-84
pubmed: 23829351
Int J Mol Sci. 2013 Jul 24;14(8):15260-85
pubmed: 23887651
J Invest Dermatol. 2007 Mar;127(3):646-53
pubmed: 17008872