Abstract
Vascular cell senescence, induced by the DNA damage response or inflammatory stress, contributes to age-associated vascular disease. Using complementary DNA microarray technology, we found that the level of POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) is downregulated during endothelial cell (EC) senescence. PATZ1 may have an important role as a transcriptional repressor in chromatin remodeling and transcription regulation; however, the role of PATZ1 in EC senescence and vascular aging remains unidentified. Knockdown of PATZ1 in young cells accelerated premature EC senescence, which was confirmed by growth arrest, increased p53 protein level and senescence-associated β-galactosidase (SA-β-gal) activity, and repression of EC tube formation. In contrast, overexpression of PATZ1 in senescent cells reversed senescent phenotypes. Cellular senescence induced by PATZ1 knockdown in young cells was rescued by knockdown of p53, but not by knockdown of p16INK4a. PATZ1 knockdown increased ROS levels, and pretreatment with N-acetylcysteine abolished EC senescence induced by PATZ1 knockdown. Notably, PATZ1 immunoreactivity was lower in ECs of atherosclerotic tissues than those of normal arteries in LDLR−/− mice, and immunoreactivity also decreased in ECs of old human arteries. These results suggest that PATZ1 may have an important role in the regulation of EC senescence through an ROS-mediated p53-dependent pathway and contribute to vascular diseases associated with aging.
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Accession codes
Abbreviations
- PATZ1:
-
POZ/BTB and AT-hook-containing zinc finger protein 1
- POZ:
-
Poxvirus zinc finger
- BTB:
-
Bric-a-brac, Tramtrack, Broad-complex
- SA-β-gal:
-
senescence-associated β-galactosidase
- HUVEC:
-
human umbilical vascular endothelial cell
- HDF:
-
human dermal fibroblast
- HDMEC:
-
human dermal microvascular endothelial cell
- RT-PCR:
-
reverse transcription polymerase chain reaction
- p53:
-
tumor protein p53
- ATM:
-
Ataxia telangiectasia mutated
- Rb:
-
retinoblastoma protein
- siRNA:
-
small interfering RNA
- shRNA:
-
small hairpin RNA
- NAC:
-
N-acetylcysteine
- MnSOD:
-
manganese superoxide dismutase
- ROS:
-
reactive oxygen species
- H2AX:
-
H2A histone member X
- LDLR:
-
low density lipoprotein receptor.
References
Collado M, Serrano M . The power and the promise of oncogene-induced senescence markers. Nat Rev Cancer 2006; 6: 472–476.
Hayflick L, Moorhead PS . The serial cultivation of human diploid cell strains. Exp Cell Res 1961; 25: 585–621.
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92: 9363–9367.
Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW . Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 1997; 88: 593–602.
Fumagalli M, d’Adda di Fagagna F . SASPense and DDRama in cancer and ageing. Nat Cell Biol 2009; 11: 921–923.
Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003; 113: 703–716.
Kuilman T, Peeper DS . Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 2009; 9: 81–94.
Campisi J, d’Adda di Fagagna F . Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8: 729–740.
Collado M, Blasco MA, Serrano M . Cellular senescence in cancer and aging. Cell 2007; 130: 223–233.
Jeyapalan JC, Sedivy JM . Cellular senescence and organismal aging. Mech Ageing Dev 2008; 129: 467–474.
Pero R, Lembo F, Palmieri EA, Vitiello C, Fedele M, Fusco A et al. PATZ attenuates the RNF4-mediated enhancement of androgen receptor-dependent transcription. J Biol Chem 2002; 277: 3280–3285.
Tian X, Sun D, Zhang Y, Zhao S, Xiong H, Fang J . Zinc finger protein 278, a potential oncogene in human colorectal cancer. Acta Biochim Biophys Sin (Shanghai) 2008; 40: 289–296.
Kobayashi A, Yamagiwa H, Hoshino H, Muto A, Sato K, Morita M et al. A combinatorial code for gene expression generated by transcription factor Bach2 and MAZR (MAZ-related factor) through the BTB/POZ domain. Mol Cell Biol 2000; 20: 1733–1746.
Fedele M, Benvenuto G, Pero R, Majello B, Battista S, Lembo F et al. A novel member of the BTB/POZ family, PATZ, associates with the RNF4 RING finger protein and acts as a transcriptional repressor. J Biol Chem 2000; 275: 7894–7901.
Bilic I, Koesters C, Unger B, Sekimata M, Hertweck A, Maschek R et al. Negative regulation of CD8 expression via Cd8 enhancer-mediated recruitment of the zinc finger protein MAZR. Nat Immunol 2006; 7: 392–400.
Mastrangelo T, Modena P, Tornielli S, Bullrich F, Testi MA, Mezzelani A et al. A novel zinc finger gene is fused to EWS in small round cell tumor. Oncogene 2000; 19: 3799–3804.
Fedele M, Franco R, Salvatore G, Paronetto MP, Barbagallo F, Pero R et al. PATZ1 gene has a critical role in the spermatogenesis and testicular tumours. J Pathol 2008; 215: 39–47.
Esposito F, Boscia F, Franco R, Tornincasa M, Fusco A, Kitazawa S et al. Down-regulation of oestrogen receptor-beta associates with transcriptional co-regulator PATZ1 delocalization in human testicular seminomas. J Pathol 2011; 224: 110–120.
Wagner M, Hampel B, Bernhard D, Hala M, Zwerschke W, Jansen-Durr P . Replicative senescence of human endothelial cells in vitro involves G1 arrest, polyploidization and senescence-associated apoptosis. Exp Gerontol 2001; 36: 1327–1347.
Atadja P, Wong H, Garkavtsev I, Veillette C, Riabowol K . Increased activity of p53 in senescing fibroblasts. Proc Natl Acad Sci USA 1995; 92: 8348–8352.
Akhtar N, Dickerson EB, Auerbach R . The sponge/Matrigel angiogenesis assay. Angiogenesis 2002; 5: 75–80.
Tritz R, Mueller BM, Hickey MJ, Lin AH, Gomez GG, Hadwiger P et al. siRNA Down-regulation of the PATZ1 Gene in Human Glioma Cells Increases Their Sensitivity to Apoptotic Stimuli. Cancer Ther 2008; 6: 865–876.
Ye X, Zerlanko B, Zhang R, Somaiah N, Lipinski M, Salomoni P et al. Definition of pRB- and p53-dependent and -independent steps in HIRA/ASF1a-mediated formation of senescence-associated heterochromatin foci. Mol Cell Biol 2007; 27: 2452–2465.
Kelly KF, Daniel JM . POZ for effect--POZ-ZF transcription factors in cancer and development. Trends Cell Biol 2006; 16: 578–587.
Doulatov S, Notta F, Rice KL, Howell L, Zelent A, Licht JD et al. PLZF is a regulator of homeostatic and cytokine-induced myeloid development. Genes Dev 2009; 23: 2076–2087.
Joko T, Nanba D, Shiba F, Miyata K, Shiraishi A, Ohashi Y et al. Effects of promyelocytic leukemia zinc finger protein on the proliferation of cultured human corneal endothelial cells. Mol Vis 2007; 13: 649–658.
Dohi Y, Ikura T, Hoshikawa Y, Katoh Y, Ota K, Nakanome A et al. Bach1 inhibits oxidative stress-induced cellular senescence by impeding p53 function on chromatin. Nat Struct Mol Biol 2008; 15: 1246–1254.
Jeon BN, Choi WI, Yu MY, Yoon AR, Kim MH, Yun CO et al. ZBTB2, a novel master regulator of the p53 pathway. J Biol Chem 2009; 284: 17935–17946.
Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB . Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 2005; 123: 437–448.
Maeda T, Hobbs RM, Merghoub T, Guernah I, Zelent A, Cordon-Cardo C et al. Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature 2005; 433: 278–285.
Maeda T, Hobbs RM, Pandolfi PP . The transcription factor Pokemon: a new key player in cancer pathogenesis. Cancer Res 2005; 65: 8575–8578.
Bartek J, Bartkova J, Lukas J . DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 2007; 26: 7773–7779.
Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G . DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation. Mol Biol Cell 2006; 17: 1583–1592.
Kim KS, Kang KW, Seu YB, Baek SH, Kim JR . Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells. Mech Ageing Dev 2009; 130: 179–188.
Ota H, Akishita M, Eto M, Iijima K, Kaneki M, Ouchi Y . Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J Mol Cell Cardiol 2007; 43: 571–579.
Minamino T, Komuro I . Vascular cell senescence: contribution to atherosclerosis. Circ Res 2007; 100: 15–26.
Ross R . Atherosclerosis--an inflammatory disease. New Eng J Med 1999; 340: 115–126.
Andreassi MG . DNA damage, vascular senescence and atherosclerosis. J Mol Med (Berlin, Germany) 2008; 86: 1033–1043.
Kim KS, Kim MS, Seu YB, Chung HY, Kim JH, Kim JR . Regulation of replicative senescence by insulin-like growth factor-binding protein 3 in human umbilical vein endothelial cells. Aging cell 2007; 6: 535–545.
Cawthon RM . Telomere measurement by quantitative PCR. Nucleic Acids Res 2002; 30: e47.
Acknowledgements
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2011-0001241).
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Cho, J., Kim, M., Kim, K. et al. POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) inhibits endothelial cell senescence through a p53 dependent pathway. Cell Death Differ 19, 703–712 (2012). https://doi.org/10.1038/cdd.2011.142
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DOI: https://doi.org/10.1038/cdd.2011.142
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