Telomerase RNA TERC and the PI3K-AKT pathway form a positive feedback loop to regulate cell proliferation independent of telomerase activity.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
22 04 2022
22 04 2022
Historique:
accepted:
16
03
2022
revised:
11
02
2022
received:
29
09
2021
pubmed:
25
3
2022
medline:
26
4
2022
entrez:
24
3
2022
Statut:
ppublish
Résumé
The core catalytic unit of telomerase comprises telomerase reverse transcriptase (TERT) and telomerase RNA (TERC). Unlike TERT, which is predominantly expressed in cancer and stem cells, TERC is ubiquitously expressed in normal somatic cells without telomerase activity. However, the functions of TERC in these telomerase-negative cells remain elusive. Here, we reported positive feedback regulation between TERC and the PI3K-AKT pathway that controlled cell proliferation independent of telomerase activity in human fibroblasts. Mechanistically, we revealed that TERC activated the transcription of target genes from the PI3K-AKT pathway, such as PDPK1, by targeting their promoters. Overexpression of PDPK1 partially rescued the deficiency of AKT activation caused by TERC depletion. Furthermore, we found that FOXO1, a transcription factor negatively regulated by the PI3K-AKT pathway, bound to TERC promoter and suppressed its expression. Intriguingly, TERC-induced activation of the PI3K-AKT pathway also played a critical role in the proliferation of activated CD4+ T cells. Collectively, our findings identify a novel function of TERC that regulates the PI3K-AKT pathway via positive feedback to elevate cell proliferation independent of telomerase activity and provide a potential strategy to promote CD4+ T cells expansion that is responsible for enhancing adaptive immune reactions to defend against pathogens and tumor cells.
Identifiants
pubmed: 35323972
pii: 6552055
doi: 10.1093/nar/gkac179
pmc: PMC9023280
doi:
Substances chimiques
telomerase RNA
0
RNA
63231-63-0
3-Phosphoinositide-Dependent Protein Kinases
EC 2.7.11.1
PDPK1 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Telomerase
EC 2.7.7.49
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3764-3776Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
Cell Rep. 2018 Sep 4;24(10):2589-2595
pubmed: 30184494
Elife. 2018 Sep 10;7:
pubmed: 30198844
Mol Cell. 2014 Mar 20;53(6):855-6
pubmed: 24656125
Eur J Immunol. 1993 Oct;23(10):2572-7
pubmed: 8405057
Signal Transduct Target Ther. 2020 Sep 21;5(1):209
pubmed: 32958760
Genes Dis. 2020 Jul 18;8(3):287-297
pubmed: 33997176
Microbiol Mol Biol Rev. 2002 Sep;66(3):407-25, table of contents
pubmed: 12208997
Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):9063-8
pubmed: 27457956
Am J Med Genet C Semin Med Genet. 2016 Dec;172(4):402-421
pubmed: 27860216
Sci Rep. 2017 Jul 28;7(1):6785
pubmed: 28754961
Curr Protoc Bioinformatics. 2016 Jun 20;54:1.30.1-1.30.33
pubmed: 27322403
Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5
pubmed: 27079975
Protein Cell. 2019 Sep;10(9):631-648
pubmed: 30788732
Nucleic Acids Res. 2019 Sep 5;47(15):8084-8095
pubmed: 31294790
Clin Cancer Res. 1998 Jul;4(7):1603-8
pubmed: 9676833
Blood. 2014 Dec 11;124(25):3675-84
pubmed: 25320237
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Cells. 2020 Jan 14;9(1):
pubmed: 31947601
Methods Mol Biol. 2019;1890:1-9
pubmed: 30414140
EMBO Rep. 2020 Apr 3;21(4):e48791
pubmed: 32133736
Cancer Cell. 2005 Feb;7(2):193-204
pubmed: 15710331
Cancer Res. 2008 Nov 15;68(22):9404-12
pubmed: 19010915
Mol Cell. 2011 May 6;42(3):297-307
pubmed: 21549308
Nucleic Acids Res. 2017 Jan 4;45(D1):D51-D55
pubmed: 27899657
Cell. 1999 Mar 19;96(6):857-68
pubmed: 10102273
Proc Natl Acad Sci U S A. 2021 Aug 10;118(32):
pubmed: 34353901
Eur J Cancer. 1997 Apr;33(5):787-91
pubmed: 9282118
Nat Rev Mol Cell Biol. 2013 Feb;14(2):69-82
pubmed: 23299958
Bioinformatics. 2009 Oct 1;25(19):2605-6
pubmed: 19689956
Science. 2002 May 31;296(5573):1655-7
pubmed: 12040186
Cold Spring Harb Perspect Biol. 2011 May 01;3(5):
pubmed: 20660025
Clin Dev Immunol. 2012;2012:925135
pubmed: 22474485
Mol Med Rep. 2019 Feb;19(2):783-791
pubmed: 30535469
Int J Cancer. 1996 Feb 20;69(1):17-22
pubmed: 8600053
Genes Dev. 2006 Oct 15;20(20):2848-58
pubmed: 17015423
Mol Biol Cell. 2008 Sep;19(9):3793-800
pubmed: 18562689
Trends Immunol. 2018 Jun;39(6):489-502
pubmed: 29452982
Blood. 2005 Feb 15;105(4):1742-9
pubmed: 15507522
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
J Cell Biochem. 2019 Jun;120(6):10248-10272
pubmed: 30592328
Pharmacogenomics. 2013 Nov;14(14):1793-803
pubmed: 24192126
J Biol Chem. 1999 Jun 11;274(24):16741-6
pubmed: 10358014
Mol Cell Biol. 2005 Nov;25(21):9543-53
pubmed: 16227604
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):183-8
pubmed: 12518064
Cancer Res. 2019 Mar 15;79(6):1019-1031
pubmed: 30808672
Nucleic Acids Res. 2009 Jan;37(1):1-13
pubmed: 19033363
Nucleic Acids Res. 2009 Oct;37(18):6105-15
pubmed: 19656952
J Immunol. 1997 Apr 1;158(7):3215-20
pubmed: 9120276
Cell. 2017 Apr 20;169(3):381-405
pubmed: 28431241
Cell. 1989 Nov 3;59(3):521-9
pubmed: 2805070
J Clin Oncol. 2005 May 10;23(14):3227-34
pubmed: 15886310
Mol Cell. 2011 Nov 18;44(4):667-78
pubmed: 21963238
Curr Biol. 1997 Apr 1;7(4):261-9
pubmed: 9094314
Nature. 2006 May 25;441(7092):431-6
pubmed: 16724054
Nat Commun. 2018 Nov 9;9(1):4728
pubmed: 30413706
J Vis Exp. 2012 Mar 25;(61):
pubmed: 22472705
J Biol Chem. 2006 Dec 29;281(52):40503-14
pubmed: 17098743
Science. 2005 Feb 18;307(5712):1098-101
pubmed: 15718470
Cancer Res. 1998 Apr 1;58(7):1558-61
pubmed: 9537264
Leukemia. 2007 Dec;21(12):2456-62
pubmed: 17898784
Nature. 1994 May 26;369(6478):327-9
pubmed: 8183372