Obsah souboru
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<JournalPrintISSN>1214-021X</JournalPrintISSN>
<JournalElectronicISSN>1214-0287</JournalElectronicISSN>
<JournalTitle>Journal of Applied Biomedicine</JournalTitle>
<JournalCode>JAB</JournalCode>
<JournalID>121649</JournalID>
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<VolumeNumber>9</VolumeNumber>
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<CoverDate Year="2011" Month="3" Day="1"/>
<CoverDisplay>Number 1 / March 2011</CoverDisplay>
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<Article ArticleType="Original">
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<ArticleDOI>10.2478/v10136-009-0031-7</ArticleDOI>
<ArticlePII>451175J641122359</ArticlePII>
<ArticleSequenceNumber>4</ArticleSequenceNumber>
<ArticleTitle Language="En">Caffeine-suppressed ATM pathway leads to decreased p53 phosphorylation and increased programmed cell death in gamma-irradiated leukaemic molt-4 cells</ArticleTitle>
<ArticleFirstPage>49</ArticleFirstPage>
<ArticleLastPage>56</ArticleLastPage>
<ArticleHistory>
<RegistrationDate>20101206</RegistrationDate>
<ReceivedDate>20101206</ReceivedDate>
<Accepted>20101206</Accepted>
<OnlineDate>20101206</OnlineDate>
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<AuthorGroup>
<Author AffiliationID="A1 A3">
<GivenName>Aleš</GivenName>
<Initials/>
<FamilyName>Tichý</FamilyName>
<Degrees/>
<Roles/>
</Author>
<Author AffiliationID="A3">
<GivenName>Darina</GivenName>
<Initials/>
<FamilyName>Muthná</FamilyName>
<Degrees/>
<Roles/>
</Author>
<Author AffiliationID="A1">
<GivenName>Jiřina</GivenName>
<Initials/>
<FamilyName>Vávrová</FamilyName>
<Degrees/>
<Roles/>
</Author>
<Author AffiliationID="A2">
<GivenName>Jaroslav</GivenName>
<Initials/>
<FamilyName>Pejchal</FamilyName>
<Degrees/>
<Roles/>
</Author>
<Author AffiliationID="A1">
<GivenName>Zuzana</GivenName>
<Initials/>
<FamilyName>Šinkorová</FamilyName>
<Degrees/>
<Roles/>
</Author>
<Author AffiliationID="A1">
<GivenName>Lenka</GivenName>
<Initials/>
<FamilyName>Zárybnická</FamilyName>
<Degrees/>
<Roles/>
</Author>
<Author AffiliationID="A3">
<GivenName>Martina</GivenName>
<Initials/>
<FamilyName>Řezáčová</FamilyName>
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<Roles/>
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<Affiliation AFFID="A1">
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<OrgName>Department of Radiobiology, University of Defence in Brno, Czech Republic</OrgName>
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<Affiliation AFFID="A2">
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<OrgName>Centre of Advanced Studies, Faculty of Military Health Sciences in Hradec Králové, University of Defence in Brno, Czech Republic</OrgName>
<OrgAddress/>
</Affiliation>
<Affiliation AFFID="A3">
<OrgDivision/>
<OrgName>Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University in Prague, Czech Republic</OrgName>
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<Abstract Language="En">Ionising radiation (IR) is one of the main treatment modalities in oncology. However, we still search for substances which can radio-sensitize tumour cells. In this study we used caffeine, a non-specific ataxia-telangiectasia mutated kinase (ATM) inhibitor, and studied its effect on the activation of the proteins involved in cell cycle control and the induction of apoptosis in human T-lymphocyte leukaemic MOLT-4 cells (p53 wt). We evaluated the expression of the tumour-suppressor p53 (itself and phosphorylated on Ser<sup>15</sup> and Ser<sup>392</sup>), the cell cycle regulator p21, and the anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1). After treatment with 2 mM caffeine, the cells were irradiated by 1 or 3 Gy, lysed and the proteins detected by Western-blotting. Apoptosis was determined by flow-cytometric annexin V/propidium iodine detection. Irradiation by 1 or 3 Gy induced p53 phosphorylation at Ser<sup>15</sup> and Ser<sup>392</sup> after 2 h with maximum after 4 h. Adding caffeine significantly inhibited Ser<sup>15</sup> phosphorylation, which is ATM-dependent but surprisingly also Ser<sup>392</sup> phosphorylation, which is ATM-independent, suggesting that caffeine might have another cellular target (protein kinase). Similarly, caffeine caused a substantial decrease in p21 in combination with both doses of IR and also Mcl-1 was down-regulated. Three days after irradiation, caffeine significantly increased induction of apoptosis. The ATM/p53 pathway was suppressed by caffeine, which led to increased apoptosis accompanied by a p53-independent decrease in Mcl-1. It also caused down-regulation of p21, which possibly contributed to the shortened cell cycle arrest necessary for effective DNA repair and thus impeded radio-resistance. Caffeine promotes the cytotoxic effect of ionising radiation and provides a possible platform for the development of new anti-cancer therapeutics known as radio-sensitizers.</Abstract>
<KeywordGroup Language="En">
<Keyword>ATM</Keyword>
</KeywordGroup>
<KeywordGroup Language="En">
<Keyword>p53</Keyword>
</KeywordGroup>
<KeywordGroup Language="En">
<Keyword>p21</Keyword>
</KeywordGroup>
<KeywordGroup Language="En">
<Keyword>Mcl-1</Keyword>
</KeywordGroup>
<KeywordGroup Language="En">
<Keyword>caffeine</Keyword>
</KeywordGroup>
<KeywordGroup Language="En">
<Keyword>ionising radiation</Keyword>
</KeywordGroup>
<KeywordGroup Language="En">
<Keyword>MOLT-4</Keyword>
</KeywordGroup>
<biblist>
<bib-other>
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</bib-other>
<bib-other>
<bibtext seqNum="2"> Bakkenist C, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimmer dissociation. Nature. 421: 499-506, 2003.</bibtext>
</bib-other>
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<bibtext seqNum="3"> Bartek J, Lukas J. Pathways governing G1/S transition and their response to DNA damage. FEBS Lett. 490: 117-122, 2001.</bibtext>
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<bib-other>
<bibtext seqNum="4"> Blasina A, Price BD, Turenne GA, McGowan CH. Caffeine inhibits the checkpoint kinase ATM. Curr Biol. 9: 1135-1138, 1999.</bibtext>
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<bibtext seqNum="5"> Block WD, Merkle D, Meek K, Lees-Miller SP. Selective inhibition of the DNA-dependent protein kinase (DNA-PK) by the radiosensitizing agent caffeine. Nucl Acids Res. 32: 1967-1972, 2004.</bibtext>
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<bib-other>
<bibtext seqNum="6"> Borner C. The Bcl-2 protein family: Sensors and checkpoints for life-or-death decisions. Mol Immunol. 39: 615-647, 2003.</bibtext>
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<bib-other>
<bibtext seqNum="7"> Claudio PP, Cui J, Ghafouri M, Mariano C, White MK, Safak M, Sheffield JB, Giordano A, Khalili K, Amini S, Sawaya BE. Cdk9 phosphorylates p53 on serine 392 independently of CKII. J Cell Physiol. 208: 602-612, 2006.</bibtext>
</bib-other>
<bib-other>
<bibtext seqNum="8"> Cortez D. Caffeine inhibits checkpoint responses without inhibiting the ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) protein kinases. J Biol Chem. 278: 37139-37145, 2003.</bibtext>
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<bibtext seqNum="18"> Khanna KK, Lavin MF, Jackson SP, Mulhern TD. ATM, a central controller of cellular responses to DNA damage. Cell Death Differ. 8: 1052-1065, 2001.</bibtext>
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<bibtext seqNum="20"> Lavin MF, Khanna KK, Beamish H, Spring K, Watters D, Shiloh Y. Relationship of the ataxia-telangiectasia protein ATM to phosphoinositide 3-kinase. Trends Biochem Sci. 20: 382-383, 1995.</bibtext>
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</biblist>
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