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Longevity & Healthspan
Published in: Longevity & Healthspan 1/2014

Open Access 01-12-2014 | Research

The secreted protein S100A7 (psoriasin) is induced by telomere dysfunction in human keratinocytes independently of a DNA damage response and cell cycle regulators

Authors: Alice de Castro, Fay Minty, Eva Hattinger, Ronald Wolf, Eric Kenneth Parkinson

Published in: Longevity & Healthspan | Issue 1/2014

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Abstract

Background

Replicative senescence is preceded by loss of repeat sequences of DNA from the telomeres that eventually leads to telomere dysfunction, the accumulation of irreparable DNA double strand breaks and a DNA damage response (DDR). However, we have previously reported that whilst telomere dysfunction in human keratinocytes is associated with a permanent cell cycle arrest, the DDR was very weak and transcriptional profiling also revealed several molecules normally associated with keratinocytes terminal differentiation, including S100A7 (psoriasin).

Results

We show here that S100A7 and the closely related S100A15 (koebnerisin) are not induced by repairable or irreparable DSBs, ruling out the hypotheses that these genes are induced either by the low DDR observed or by non-specific cell cycle arrest. We next tested whether S100A7 was induced by the cell cycle effectors ARF (p14ARF), CDKN2A (p16INK4A) and TP53 (p53) and found that, although all induced a similar level of acute and permanent cell cycle arrest to telomere dysfunction, none induced S100A7 (except p53 over-expression at high levels), showing that cell cycle arrest is not sufficient for its induction. The closely related transcript S100A15 was also upregulated by telomere dysfunction, to a similar extent by p16INK4A and p53 and to a lesser extent by p14ARF.

Conclusions

Our results show that mere cell cycle arrest, the upregulation of senescence-associated cell cycle effectors and DNA damage are not sufficient for the induction of the S100 transcripts; they further suggest that whilst the induction of S100A15 expression is linked to both telomere-dependent and -independent senescence, S100A7 expression is specifically associated with telomere-dependent senescence in normal keratinocytes. As both S100A7 and S100A15 are secreted proteins, they may find utility in the early detection of human keratinocyte telomere dysfunction and senescence.
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Literature
1.
Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J: Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008, 6: 2853-2868.CrossRefPubMed
2.
Kuilman T, Peeper DS: Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer. 2009, 9: 81-94. 10.1038/nrc2560.CrossRefPubMed
3.
Jiang H, Schiffer E, Song Z, Wang J, Zurbig P, Thedieck K, Moes S, Bantel H, Saal N, Jantos J, Brecht M, Jeno P, Hall MN, Hager K, Manns MP, Hecker H, Ganser A, Dohner K, Bartke A, Meissner C, Mischak H, Ju Z, Rudolph KL: Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease. Proc Natl Acad Sci U S A. 2008, 105: 11299-11304. 10.1073/pnas.0801457105.PubMedCentralCrossRefPubMed
4.
Harley CB, Futcher AB, Greider CW: Telomeres shorten during ageing of human fibroblasts. Nature. 1990, 345: 458-460. 10.1038/345458a0.CrossRefPubMed
5.
De Lange T: How shelterin solves the telomere end-protection problem. Cold Spring Harb Symp Quant Biol. 2010, 75: 167-177. 10.1101/sqb.2010.75.017.CrossRefPubMed
6.
De Lange T: Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005, 19: 2100-2110. 10.1101/gad.1346005.CrossRefPubMed
7.
Olovnikov AM: A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol. 1973, 41: 181-190. 10.1016/0022-5193(73)90198-7.CrossRefPubMed
8.
9.
Makarov VL, Hirose Y, Langmore JP: Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell. 1997, 88: 657-666. 10.1016/S0092-8674(00)81908-X.CrossRefPubMed
10.
Petersen S, Saretzki G, Von Zglinicki T: Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp Cell Res. 1998, 239: 152-160. 10.1006/excr.1997.3893.CrossRefPubMed
11.
Von Zglinicki T, Saretzki G, Docke W, Lotze C: Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence?. Exp Cell Res. 1995, 220: 186-193. 10.1006/excr.1995.1305.CrossRefPubMed
12.
Takai H, Smogorzewska A, De Lange T: DNA damage foci at dysfunctional telomeres. Curr Biol. 2003, 13: 1549-1556. 10.1016/S0960-9822(03)00542-6.CrossRefPubMed
13.
D’Adda Di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP: A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003, 426: 194-198. 10.1038/nature02118.CrossRefPubMed
14.
Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov JM, Bucci G, Dobreva M, Matti V, Beausejour CM, Herbig U, Longhese MP, D’Adda Di Fagagna F: Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol. 2012, 14: 355-365. 10.1038/ncb2466.PubMedCentralCrossRefPubMed
15.
Hewitt G, Jurk D, Marques FD, Correia-Melo C, Hardy T, Gackowska A, Anderson R, Taschuk M, Mann J, Passos JF: Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun. 2012, 3: 708-PubMedCentralCrossRefPubMed
16.
Mao L, El-Naggar AK, Fan YH, Lee JS, Lippman SM, Kayser S, Lotan R, Hong WK: Telomerase activity in head and neck squamous cell carcinoma and adjacent tissues. Cancer Res. 1996, 56: 5600-5604.PubMed
17.
Rheinwald JG, Hahn WC, Ramsey MR, Wu JY, Guo Z, Tsao H, De Luca M, Catricala C, O’Toole KM: A two-stage, p16(INK4A)- and p53-dependent keratinocyte senescence mechanism that limits replicative potential independent of telomere status. Mol Cell Biol. 2002, 22: 5157-5172. 10.1128/MCB.22.14.5157-5172.2002.PubMedCentralCrossRefPubMed
18.
Suram A, Kaplunov J, Patel PL, Ruan H, Cerutti A, Boccardi V, Fumagalli M, Di Micco R, Mirani N, Gurung RL, Hande MP, D’Adda Di Fagagna F, Herbig U: Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J. 2012, 31: 2839-2851. 10.1038/emboj.2012.132.PubMedCentralCrossRefPubMed
19.
Giangreco A, Qin M, Pintar JE, Watt FM: Epidermal stem cells are retained in vivo throughout skin aging. Aging Cell. 2008, 7: 250-259. 10.1111/j.1474-9726.2008.00372.x.PubMedCentralCrossRefPubMed
20.
Sharpless NE, DePinho RA: How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol. 2007, 8: 703-713. 10.1038/nrm2241.CrossRefPubMed
21.
Barrandon Y, Green H: Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci U S A. 1987, 84: 2302-2306. 10.1073/pnas.84.8.2302.PubMedCentralCrossRefPubMed
22.
Lindsey J, McGill NI, Lindsey LA, Green DK, Cooke HJ: In vivo loss of telomeric repeats with age in humans. Mutat Res. 1991, 256: 45-48. 10.1016/0921-8734(91)90032-7.CrossRefPubMed
23.
Nakamura K, Izumiyama-Shimomura N, Sawabe M, Arai T, Aoyagi Y, Fujiwara M, Tsuchiya E, Kobayashi Y, Kato M, Oshimura M, Sasajima K, Nakachi K, Takubo K: Comparative analysis of telomere lengths and erosion with age in human epidermis and lingual epithelium. J Invest Dermatol. 2002, 119: 1014-1019. 10.1046/j.1523-1747.2002.19523.x.CrossRefPubMed
24.
Sugimoto M, Yamashita R, Ueda M: Telomere length of the skin in association with chronological aging and photoaging. J Dermatol Sci. 2006, 43: 43-47. 10.1016/j.jdermsci.2006.02.004.CrossRefPubMed
25.
Ressler S, Bartkova J, Niederegger H, Bartek J, Scharffetter-Kochanek K, Jansen-Durr P, Wlaschek M: p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell. 2006, 5: 379-389. 10.1111/j.1474-9726.2006.00231.x.CrossRefPubMed
26.
Waaijer ME, Parish WE, Strongitharm BH, Van Heemst D, Slagboom PE, De Craen AJ, Sedivy JM, Westendorp RG, Gunn DA, Maier AB: The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell. 2012, 11: 722-725. 10.1111/j.1474-9726.2012.00837.x.PubMedCentralCrossRefPubMed
27.
28.
Minty F, Thurlow JK, Harrison PR, Parkinson EK: Telomere dysfunction in human keratinocytes elicits senescence and a novel transcription profile. Exp Cell Res. 2008, 314: 2434-2447. 10.1016/j.yexcr.2008.05.007.CrossRefPubMed
29.
Zhang H, Zhao Q, Chen Y, Wang Y, Gao S, Mao Y, Li M, Peng A, He D, Xiao X: Selective expression of S100A7 in lung squamous cell carcinomas and large cell carcinomas but not in adenocarcinomas and small cell carcinomas. Thorax. 2008, 63: 352-359. 10.1136/thx.2007.087015.CrossRefPubMed
30.
Wang J, Sun Q, Morita Y, Jiang H, Gross A, Lechel A, Hildner K, Guachalla LM, Gompf A, Hartmann D, Schambach A, Wuestefeld T, Dauch D, Schrezenmeier H, Hofmann WK, Nakauchi H, Ju Z, Kestler HA, Zender L, Rudolph KL: A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage. Cell. 2012, 148: 1001-1014. 10.1016/j.cell.2012.01.040.CrossRefPubMed
31.
Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J: Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009, 11: 973-979. 10.1038/ncb1909.PubMedCentralCrossRefPubMed
32.
Dulic V, Drullinger LF, Lees E, Reed SI, Stein GH: Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin E-Cdk2 and cyclin D1-Cdk2 complexes. Proc Natl Acad Sci U S A. 1993, 90: 11034-11038. 10.1073/pnas.90.23.11034.PubMedCentralCrossRefPubMed
33.
Topley GI, Okuyama R, Gonzales JG, Conti C, Dotto GP: p21(WAF1/Cip1) functions as a suppressor of malignant skin tumor formation and a determinant of keratinocyte stem-cell potential. Proc Natl Acad Sci U S A. 1999, 96: 9089-9094. 10.1073/pnas.96.16.9089.PubMedCentralCrossRefPubMed
34.
Missero C, Di Cunto F, Kiyokawa H, Koff A, Dotto GP: The absence of p21Cip1/WAF1 alters keratinocyte growth and differentiation and promotes ras-tumor progression. Genes Dev. 1996, 10: 3065-3075. 10.1101/gad.10.23.3065.CrossRefPubMed
35.
Wolf R, Mirmohammadsadegh A, Walz M, Lysa B, Tartler U, Remus R, Hengge U, Michel G, Ruzicka T: Molecular cloning and characterization of alternatively spliced mRNA isoforms from psoriatic skin encoding a novel member of the S100 family. FASEB J. 2003, 17: 1969-1971.PubMed
36.
Wolf R, Ruzicka T, Yuspa SH: Novel S100A7 (psoriasin)/S100A15 (koebnerisin) subfamily: highly homologous but distinct in regulation and function. Amino Acids. 2011, 41: 789-796. 10.1007/s00726-010-0666-4.CrossRefPubMed
37.
Panier S, Ichijima Y, Fradet-Turcotte A, Leung CC, Kaustov L, Arrowsmith CH, Durocher D: Tandem protein interaction modules organize the ubiquitin-dependent response to DNA double-strand breaks. Mol Cell. 2012, 47: 383-395. 10.1016/j.molcel.2012.05.045.CrossRefPubMed
38.
Shiloh Y, Shema E, Moyal L, Oren M: RNF20-RNF40: a ubiquitin-driven link between gene expression and the DNA damage response. FEBS Lett. 2011, 585: 2795-2802. 10.1016/j.febslet.2011.07.034.CrossRefPubMed
39.
Muntoni A, Fleming J, Gordon KE, Hunter K, McGregor F, Parkinson EK, Harrison PR: Senescing oral dysplasias are not immortalized by ectopic expression of hTERT alone without other molecular changes, such as loss of INK4A and/or retinoic acid receptor-beta: but p53 mutations are not necessarily required. Oncogene. 2003, 22: 7804-7808. 10.1038/sj.onc.1207085.CrossRefPubMed
40.
Coppe JP, Rodier F, Patil CK, Freund A, Desprez PY, Campisi J: Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J Biol Chem. 2011, 286: 36396-36403. 10.1074/jbc.M111.257071.PubMedCentralCrossRefPubMed
41.
Blanco R, Munoz P, Flores JM, Klatt P, Blasco MA: Telomerase abrogation dramatically accelerates TRF2-induced epithelial carcinogenesis. Genes Dev. 2007, 21: 206-220. 10.1101/gad.406207.PubMedCentralCrossRefPubMed
42.
Biroccio A, Cherfils-Vicini J, Augereau A, Pinte S, Bauwens S, Ye J, Simonet T, Horard B, Jamet K, Cervera L, Mendez-Bermudez A, Poncet D, Grataroli R, De Rodenbeeke CT, Salvati E, Rizzo A, Zizza P, Ricoul M, Cognet C, Kuilman T, Duret H, Lepinasse F, Marvel J, Verhoeyen E, Cosset FL, Peeper D, Smyth MJ, Londono-Vallejo A, Sabatier L, Picco V, Pages G, Scoazec JY, Stoppacciaro A, Leonetti C, Vivier E, Gilson E: TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells. Nat Cell Biol. 2013, 15: 818-828. 10.1038/ncb2774.CrossRefPubMed
43.
Loughran O, Malliri A, Owens D, Gallimore PH, Stanley MA, Ozanne B, Frame MC, Parkinson EK: Association of CDKN2A/p16INK4A with human head and neck keratinocyte replicative senescence: relationship of dysfunction to immortality and neoplasia. Oncogene. 1996, 13: 561-568.PubMed
44.
Hattinger E, Zwicker S, Ruzicka T, Yuspa SH, Wolf R: Opposing functions of psoriasin (S100A7) and koebnerisin (S100A15) in epithelial carcinogenesis. Curr Opin Pharmacol. 2013, 13: 588-594. 10.1016/j.coph.2013.04.007.CrossRefPubMed
45.
Deol YS, Nasser MW, Yu L, Zou X, Ganju RK: Tumor-suppressive effects of psoriasin (S100A7) are mediated through the beta-catenin/T cell factor 4 protein pathway in estrogen receptor-positive breast cancer cells. J Biol Chem. 2011, 286: 44845-44854. 10.1074/jbc.M111.225466.PubMedCentralCrossRefPubMed
46.
Hattori F, Kiatsurayanon C, Okumura K, Ogawa H, Ikeda S, Okamoto K, Niyonsaba F: The antimicrobial protein S100A7/psoriasin enhances expression of keratinocyte differentiation markers and strengthens the skin tight junction barrier. Br J Dermatol. 2014, ᅟ: ᅟ-doi:10.1111/bjd.13125. [Epub ahead of print]
47.
Gebhardt C, Riehl A, Durchdewald M, Nemeth J, Furstenberger G, Muller-Decker K, Enk A, Arnold B, Bierhaus A, Nawroth PP, Hess J, Angel P: RAGE signaling sustains inflammation and promotes tumor development. J Exp Med. 2008, 205: 275-285. 10.1084/jem.20070679.PubMedCentralCrossRefPubMed
48.
Freund A, Patil CK, Campisi J: p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011, 30: 1536-1548. 10.1038/emboj.2011.69.PubMedCentralCrossRefPubMed
49.
Pitiyage GN, Slijepcevic P, Gabrani A, Chianea YG, Lim KP, Prime SS, Tilakaratne WM, Fortune F, Parkinson EK: Senescent mesenchymal cells accumulate in human fibrosis by a telomere-independent mechanism and ameliorate fibrosis through matrix metalloproteinases. J Pathol. 2011, 223: 604-617. 10.1002/path.2839.CrossRefPubMed
50.
Gordon KE, Ireland H, Roberts M, Steeghs K, McCaul JA, MacDonald DG, Parkinson EK: High levels of telomere dysfunction bestow a selective disadvantage during the progression of human oral squamous cell carcinoma. Cancer Res. 2003, 63: 458-467.PubMed
51.
Parris CN, Jezzard S, Silver A, MacKie R, McGregor JM, Newbold RF: Telomerase activity in melanoma and non-melanoma skin cancer. Br J Cancer. 1999, 79: 47-53. 10.1038/sj.bjc.6690010.PubMedCentralCrossRefPubMed
52.
Gschwandtner M, Zhong S, Tschachler A, Mlitz V, Karner S, Elbe-Burger A, Mildner M: Fetal human keratinocytes produce large amounts of antimicrobial peptides: involvement of histone-methylation processes. J Invest Dermatol. 2014, 134: 2192-2201. 10.1038/jid.2014.165.PubMedCentralCrossRefPubMed
53.
Yu SE, Jang YK: The histone demethylase LSD1 is required for estrogen-dependent S100A7 gene expression in human breast cancer cells. Biochem Biophys Res Commun. 2012, 427: 336-342. 10.1016/j.bbrc.2012.09.057.CrossRefPubMed
54.
Schoeftner S, Blanco R, Lopez De Silanes I, Munoz P, Gomez-Lopez G, Flores JM, Blasco MA: Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations. Proc Natl Acad Sci U S A. 2009, 106: 19393-19398. 10.1073/pnas.0909265106.PubMedCentralCrossRefPubMed
55.
Tomas-Loba A, Flores I, Fernandez-Marcos PJ, Cayuela ML, Maraver A, Tejera A, Borras C, Matheu A, Klatt P, Flores JM, Vina J, Serrano M, Blasco MA: Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell. 2008, 135: 609-622. 10.1016/j.cell.2008.09.034.CrossRefPubMed
56.
Gemenetzidis E, Bose A, Riaz AM, Chaplin T, Young BD, Ali M, Sugden D, Thurlow JK, Cheong SC, Teo SH, Wan H, Waseem A, Parkinson EK, Fortune F, Teh MT: FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation. PLoS One. 2009, 4: e4849-10.1371/journal.pone.0004849.PubMedCentralCrossRefPubMed
57.
Wolf R, Howard OM, Dong HF, Voscopoulos C, Boeshans K, Winston J, Divi R, Gunsior M, Goldsmith P, Ahvazi B, Chavakis T, Oppenheim JJ, Yuspa SH: Chemotactic activity of S100A7 (psoriasin) is mediated by the receptor for advanced glycation end products and potentiates inflammation with highly homologous but functionally distinct S100A15. J Immunol. 2008, 181: 1499-1506. 10.4049/jimmunol.181.2.1499.PubMedCentralCrossRefPubMed
Metadata
Title
The secreted protein S100A7 (psoriasin) is induced by telomere dysfunction in human keratinocytes independently of a DNA damage response and cell cycle regulators
Authors
Alice de Castro
Fay Minty
Eva Hattinger
Ronald Wolf
Eric Kenneth Parkinson
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Longevity & Healthspan / Issue 1/2014
Electronic ISSN: 2046-2395
DOI
https://doi.org/10.1186/2046-2395-3-8

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