Research Paper Volume 10, Issue 3 pp 434—462

Induction, regulation and roles of neural adhesion molecule L1CAM in cellular senescence

Blanka Mrazkova 1, , Rastislav Dzijak 1, , Terezie Imrichova 1, , Lenka Kyjacova 1, , Peter Barath 2, , Petr Dzubak 3, , Dusan Holub 3, , Marian Hajduch 3, , Zuzana Nahacka 4, , Ladislav Andera 4, , Petr Holicek 4, , Pavla Vasicova 1, , Olena Sapega 5, , Jiri Bartek 1, 6, 7, , Zdenek Hodny 1, ,

  • 1 Department of Genome Integrity, Institute of Molecular Genetics of the ASCR, Prague 14220, Czech Republic
  • 2 Institute of Chemistry, Slovak Academy of Sciences, Bratislava 84538, Slovakia
  • 3 Institute of Molecular and Translational Medicine, Palacky University, Olomouc 77147, Czech Republic
  • 4 Laboratory of Molecular Therapy, Institute of Biotechnology of the ASCR, Prague 14220, Czech Republic
  • 5 Laboratory of Immunological and Tumour Models, Institute of Molecular Genetics of the ASCR, Prague 14220, Czech Republic
  • 6 Danish Cancer Society Research Center, Copenhagen DK-2100, Denmark
  • 7 Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden

received: December 20, 2017 ; accepted: March 22, 2018 ; published: March 28, 2018 ;

https://doi.org/10.18632/aging.101404
How to Cite

Copyright: Mrazkova et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Aging involves tissue accumulation of senescent cells (SC) whose elimination through senolytic approaches may evoke organismal rejuvenation. SC also contribute to aging-associated pathologies including cancer, hence it is imperative to better identify and target SC. Here, we aimed to identify new cell-surface proteins differentially expressed on human SC. Besides previously reported proteins enriched on SC, we identified 78 proteins enriched and 73 proteins underrepresented in replicatively senescent BJ fibroblasts, including L1CAM, whose expression is normally restricted to the neural system and kidneys. L1CAM was: 1) induced in premature forms of cellular senescence triggered chemically and by gamma-radiation, but not in Ras-induced senescence; 2) induced upon inhibition of cyclin-dependent kinases by p16INK4a; 3) induced by TGFbeta and suppressed by RAS/MAPK(Erk) signaling (the latter explaining the lack of L1CAM induction in RAS-induced senescence); and 4) induced upon downregulation of growth-associated gene ANT2, growth in low-glucose medium or inhibition of the mevalonate pathway. These data indicate that L1CAM is controlled by a number of cell growth- and metabolism-related pathways during SC development. Functionally, SC with enhanced surface L1CAM showed increased adhesion to extracellular matrix and migrated faster. Our results provide mechanistic insights into senescence of human cells, with implications for future senolytic strategies.

Abbreviations

ADAMTS1: a disintegrin and metalloproteinase with thrombospondin motif 1; ANT2: adenine nucleotide translocase 2; BrdU: 5-bromo-2'-deoxyuridine; DAPI: 4',6-diamidino-2-phenylindole; FACS: fluorescence-activated cell sorting; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GGT2: gamma-glutamyltranspeptidase 2; IFNγ: interferon gamma; IL: interleukin; IR: ionizing radiation; MAPK: mitogen-activated protein kinase; MCP-1: monocyte chemotactic protein 1; NFI: nuclear factor I; NFκB: nuclear factor kappa B; PD: population doubling; PVR: poliovirus receptor; SASP: senescence-associated secretory phenotype; SA-β-gal: senescence-associated beta-galactosidase; SC: senescent cells; SMAD: small mothers against decapentaplegic; TGFβ: transforming growth factor beta; TIMP3: tissue inhibitor of metalloproteinase 3.