CDK1‑induced regulation of p53 phosphorylation at Ser315 mediates cell cycle arrest and apoptosis of macrophages infected with clinical isolates of Mycobacterium tuberculosis.

Publisher: D. A. Spandidos Country of Publication: Greece NLM ID: 101475259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1791-3004 (Electronic) Linking ISSN: 17912997 NLM ISO Abbreviation: Mol Med Rep Subsets: MEDLINE

Original Publication: Athens, Greece : D. A. Spandidos

Macrophages*/microbiology ; Macrophages*/metabolism ; Macrophages*/pathology ; Mycobacterium tuberculosis*/isolation & purification ; Tumor Suppressor Protein p53*/metabolism ; Tumor Suppressor Protein p53*/genetics ; CDC2 Protein Kinase*/metabolism ; Tuberculosis*/microbiology ; Tuberculosis*/metabolism ; Apoptosis* ; Cell Cycle Checkpoints*; Phosphorylation ; Humans ; Mice ; Animals

Tuberculosis (TB) is an infectious disease caused by infection with Mycobacterium tuberculosis (MTB). The morbidity of TB in the Xinjiang region of China is higher than that in other provinces. Macrophage apoptosis after infection with MTB is considered to serve a key role in killing the bacteria. However, the biological process of apoptosis and the underlying molecular mechanisms triggered by the infection of macrophages with clinical isolates of MTB from Xinjiang (XJMTB) are not clear. The present study aimed to investigate the unique characteristics of XJMTB. Briefly, western blotting and flow cytometry were employed in the present study, and it was demonstrated that macrophages infected with MTB H37Rv or XJMTB underwent G2/M cell cycle arrest and apoptosis. The transcriptome sequencing analysis showed that cyclin‑dependent kinase 1 (CDK1) was a key regulatory gene in regulating the G2/M cell cycle arrest and apoptosis in MTB‑infected macrophages, and the p53 gene was most likely involved in the regulation of this. Moreover, the phosphorylation of p53 (Ser315) was elevated with the upregulation of CDK1 activation, leading to a higher proportion of MTB‑infected macrophages exhibiting G2/M cell cycle block and apoptosis. The current study also revealed that enhanced activation of CDK1 reversed the attenuation of the G2/M cell cycle block and the reduction in the percentage of apoptosis caused by inhibition of p53 (Ser315) phosphorylation. Furthermore, the co‑immunoprecipitation experiment demonstrated an interaction between CDK1 and p53. The present study indicated that, in an in vitro model of macrophage infection with XJMTB, enhanced activation of CDK1 may regulate the phosphorylation of p53 (Ser315), promote the secretion of TNF‑α, IL‑6, IL‑10, IL‑1β and IL‑12, promote G2/M cell cycle arrest and apoptosis of macrophages, and enhance the survival of XJMTB in macrophages. These results provide CDK1 and phosphorylated‑p53 as two new potential therapeutic targets for TB in Xinjiang, and lay a foundation for the development of novel TB treatment strategies.

Infect Immun. 1996 Feb;64(2):452-9. (PMID: 8550191)
Nat Commun. 2020 Nov 4;11(1):5566. (PMID: 33149141)
Nat Microbiol. 2023 May;8(5):762-763. (PMID: 37142685)
Bioinformatics. 2015 Jan 15;31(2):166-9. (PMID: 25260700)
J Immunol. 2000 Dec 15;165(12):7102-8. (PMID: 11120840)
J Immunol. 2018 May 15;200(10):3506-3518. (PMID: 29661829)
Nat Immunol. 2008 Oct;9(10):1189-97. (PMID: 18794848)
Apoptosis. 2023 Feb;28(1-2):136-165. (PMID: 36258102)
Infect Immun. 2008 Jan;76(1):351-60. (PMID: 17954721)
J Exp Med. 2019 Mar 4;216(3):556-570. (PMID: 30787033)
J Immunol. 2006 Apr 1;176(7):4267-74. (PMID: 16547264)
Nat Rev Cancer. 2009 Mar;9(3):153-66. (PMID: 19238148)
Nat Rev Mol Cell Biol. 2015 Jul;16(7):393-405. (PMID: 26122615)
Genes Genomics. 2022 Oct;44(10):1191-1199. (PMID: 35951158)
Cell Microbiol. 2003 Sep;5(9):649-60. (PMID: 12925134)
Methods Mol Biol. 2016;1336:155-66. (PMID: 26231715)
PLoS One. 2017 Nov 9;12(11):e0187592. (PMID: 29121654)
J Biol Chem. 2013 Aug 23;288(34):24956-71. (PMID: 23846686)
Gene. 2019 Jun 15;701:15-22. (PMID: 30898709)
Infect Dis (Lond). 2016 Feb;48(2):108-15. (PMID: 26414438)
Front Pharmacol. 2021 May 20;12:671138. (PMID: 34093198)
Infect Immun. 1997 Dec;65(12):5272-8. (PMID: 9393826)
BMC Res Notes. 2012 Jun 19;5:309. (PMID: 22713520)
Biochem Biophys Res Commun. 2020 Jan 1;521(1):252-258. (PMID: 31653349)
Tuberculosis (Edinb). 2018 Jul;111:57-66. (PMID: 30029916)
Nat Rev Microbiol. 2022 Dec;20(12):750-766. (PMID: 35879556)
DNA Repair (Amst). 2019 Feb;74:17-25. (PMID: 30641156)
Proc Natl Acad Sci U S A. 1997 May 13;94(10):5243-8. (PMID: 9144222)
J Cardiothorac Vasc Anesth. 2018 Dec;32(6):2771-2779. (PMID: 29730239)
PLoS One. 2012;7(6):e39891. (PMID: 22768155)
Cell Death Differ. 1998 Jul;5(7):563-8. (PMID: 10200510)
Infect Immun. 2001 Apr;69(4):2001-10. (PMID: 11254551)
Methods Mol Biol. 2014;1170:29-40. (PMID: 24906307)
J Clin Immunol. 2005 Jul;25(4):353-64. (PMID: 16133992)
Traffic. 2020 Aug;21(8):522-533. (PMID: 32506678)
Cell Death Dis. 2022 Sep 27;13(9):827. (PMID: 36167685)
Aging (Albany NY). 2022 Mar 7;14(5):2174-2193. (PMID: 35256539)
Infect Immun. 1991 Sep;59(9):3213-8. (PMID: 1908829)
Nat Biotechnol. 2019 Aug;37(8):907-915. (PMID: 31375807)
Microbes Infect. 2018 Oct - Nov;20(9-10):552-559. (PMID: 29109017)
Cell Immunol. 2007 Oct;249(2):80-93. (PMID: 18160064)
Tuberculosis (Edinb). 2019 May;116:22-31. (PMID: 31153514)
PLoS One. 2012;7(6):e38878. (PMID: 22761710)
Am J Physiol Cell Physiol. 2022 Nov 1;323(5):C1444-C1474. (PMID: 36189975)
Front Cell Neurosci. 2014 Sep 30;8:281. (PMID: 25324720)
Injury. 1993 Oct;24(9):607-9. (PMID: 8288381)
Zhonghua Liu Xing Bing Xue Za Zhi. 2013 Oct;34(10):980-4. (PMID: 24377991)
Mucosal Immunol. 2011 May;4(3):279-87. (PMID: 21307848)
Front Cell Infect Microbiol. 2020 Sep 30;10:457. (PMID: 33102245)
J Infect Dis. 1997 Dec;176(6):1552-8. (PMID: 9395367)
Clin Transl Oncol. 2021 Sep;23(9):1743-1751. (PMID: 33721187)
Cell Immunol. 2020 Aug;354:104145. (PMID: 32569876)
Free Radic Biol Med. 2019 Mar;133:162-168. (PMID: 29800655)
Cancers (Basel). 2011 Mar 03;3(1):994-1013. (PMID: 24212651)
Nat Med. 2003 Aug;9(8):1039-46. (PMID: 12872166)
J Bacteriol. 2012 Jun;194(11):2916-23. (PMID: 22467787)
Cell Div. 2010 May 13;5:11. (PMID: 20465793)
Cancer Manag Res. 2020 Nov 04;12:11271-11283. (PMID: 33177877)
J Infect Dis. 2004 Sep 15;190(6):1167-76. (PMID: 15319868)
Tuberculosis (Edinb). 2020 Jan;120:101900. (PMID: 32090861)
PLoS One. 2015 Dec 07;10(12):e0144010. (PMID: 26641642)
Front Immunol. 2021 Oct 20;12:742370. (PMID: 34745115)
Apoptosis. 2020 Feb;25(1-2):42-55. (PMID: 31691131)
EMBO J. 2005 Aug 3;24(15):2768-82. (PMID: 16037820)
Curr Opin Microbiol. 2014 Feb;17:17-23. (PMID: 24581688)
J Family Community Med. 2022 May-Aug;29(2):117-124. (PMID: 35754748)
Genome Biol. 2014;15(6):122. (PMID: 25180339)
J Clin Microbiol. 2006 Jan;44(1):274-7. (PMID: 16390989)
J Cell Biol. 2011 Dec 12;195(6):931-42. (PMID: 22123830)
J Immunol. 1997 May 1;158(9):4320-7. (PMID: 9126994)
Eur Rev Med Pharmacol Sci. 2022 Mar;26(6):2049-2056. (PMID: 35363355)
Diabetes. 2005 May;54(5):1423-8. (PMID: 15855329)
Clin Exp Immunol. 2000 Dec;122(3):343-9. (PMID: 11122239)
Arch Immunol Ther Exp (Warsz). 2000;48(6):513-9. (PMID: 11197606)
Front Immunol. 2018 Apr 04;9:677. (PMID: 29670633)
Front Cell Infect Microbiol. 2016 Nov 18;6:147. (PMID: 27917375)
BMC Cancer. 2025 Jan 7;25(1):20. (PMID: 39773464)
Front Cell Infect Microbiol. 2024 Jan 19;14:1285493. (PMID: 38312744)
Mol Cell Biochem. 2023 Apr;478(4):767-780. (PMID: 36083512)
Int J Mol Sci. 2023 Aug 03;24(15):. (PMID: 37569750)
J Immunol. 2000 Jan 1;164(1):379-88. (PMID: 10605033)
Lancet. 2023 Oct 21;402(10411):1473-1498. (PMID: 37716363)
Oncogene. 2017 Jul 13;36(28):3943-3956. (PMID: 28288132)
Antimicrob Agents Chemother. 2005 Mar;49(3):1209-12. (PMID: 15728930)
J Exp Med. 1992 Apr 1;175(4):1111-22. (PMID: 1552282)
Cell Death Dis. 2021 May 22;12(6):529. (PMID: 34023852)
Trends Microbiol. 1993 Jun;1(3):114-7. (PMID: 8143119)
J Immunol. 2006 Mar 15;176(6):3707-16. (PMID: 16517739)
Nat Rev Microbiol. 2010 Sep;8(9):668-74. (PMID: 20676146)
Cell Death Discov. 2020 Aug 5;6:70. (PMID: 32802407)
J Genet Genomics. 2021 Jan 20;48(1):63-74. (PMID: 33832859)
Front Pharmacol. 2022 May 25;13:895573. (PMID: 35694267)
Lancet. 2014 Jun 14;383(9934):2057-2064. (PMID: 24650955)
Adv Biol (Weinh). 2024 Mar;8(3):e2300403. (PMID: 38103005)
Immunity. 2021 Aug 10;54(8):1625-1627. (PMID: 34380059)
Methods. 2001 Dec;25(4):402-8. (PMID: 11846609)
Microb Pathog. 1998 May;24(5):309-20. (PMID: 9600863)
Cell Immunol. 1991 Jan;132(1):150-7. (PMID: 1905984)
Science. 1999 Jul 30;285(5428):736-9. (PMID: 10426996)
Oncogene. 2009 Aug 20;28(33):2925-39. (PMID: 19561645)
BMC Bioinformatics. 2003 Jan 13;4:2. (PMID: 12525261)
Life Sci. 2021 Feb 1;266:118851. (PMID: 33310032)
Front Cell Infect Microbiol. 2014 Mar 05;4:31. (PMID: 24634891)
Annu Rev Cell Dev Biol. 1997;13:261-91. (PMID: 9442875)
Carcinogenesis. 2014 Apr;35(4):740-6. (PMID: 24381013)
PLoS One. 2023 Jan 31;18(1):e0281170. (PMID: 36719870)
Cold Spring Harb Perspect Med. 2016 Mar 01;6(3):a026104. (PMID: 26931810)
J Immunol Res. 2021 Oct 4;2021:7925903. (PMID: 34646890)
Front Microbiol. 2017 Oct 12;8:2008. (PMID: 29085351)
Biochem Biophys Res Commun. 2017 Nov 4;493(1):514-520. (PMID: 28867196)
Methods Mol Biol. 2016;1374:339-61. (PMID: 26519415)
Infect Immun. 2001 Sep;69(9):5823-31. (PMID: 11500460)
Immunity. 1997 Sep;7(3):433-44. (PMID: 9324363)
Cell Death Differ. 1999 Jan;6(1):71-8. (PMID: 10200550)
Development. 2013 Aug;140(15):3079-93. (PMID: 23861057)
Science. 1999 Jul 30;285(5428):732-6. (PMID: 10426995)
PLoS Genet. 2023 Aug 24;19(8):e1010888. (PMID: 37616312)
PLoS Pathog. 2007 Jul;3(7):e110. (PMID: 17658950)
Science. 1997 Jun 13;276(5319):1684-7. (PMID: 9180075)
Cell Host Microbe. 2017 Oct 11;22(4):519-530.e3. (PMID: 29024644)
Oncotarget. 2016 Jan 5;7(1):622-37. (PMID: 26506418)
Cold Spring Harb Perspect Med. 2014 Nov 06;5(9):. (PMID: 25377142)

Keywords: CDK1; apoptosis; cell cycle; phosphorylated‑p53; tuberculosis

0 (Tumor Suppressor Protein p53)
EC 2.7.11.22 (CDC2 Protein Kinase)
EC 2.7.11.22 (CDK1 protein, human)

Date Created: 20251121 Date Completed: 20251121 Latest Revision: 20251206

20260130

PMC12676215

10.3892/mmr.2025.13754

41268607