Počet záznamů: 1  

Immortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations

  1. 1.
    SYSNO ASEP0482266
    Druh ASEPJ - Článek v odborném periodiku
    Zařazení RIVJ - Článek v odborném periodiku
    Poddruh JČlánek ve WOS
    NázevImmortalization of normal human mammary epithelial cells in two steps by direct targeting of senescence barriers does not require gross genomic alterations
    Tvůrce(i) Garbe, J.C. (US)
    Vrba, Lukáš (BC-A)
    Sputova, K. (US)
    Fuchs, L. (US)
    Novák, Petr (BC-A) RID, ORCID
    Brothman, A.R. (US)
    Jackson, M. (US)
    Chin, K. (US)
    LaBarge, M.A. (US)
    Watts, G. (US)
    Futscher, B. W. (US)
    Stampfer, M.R. (US)
    Celkový počet autorů12
    Zdroj.dok.Cell Cycle. - : Taylor & Francis - ISSN 1538-4101
    Roč. 13, č. 21 (2014), s. 3423-3435
    Poč.str.13 s.
    Forma vydáníTištěná - P
    Jazyk dok.eng - angličtina
    Země vyd.US - Spojené státy americké
    Klíč. slovagenomic instability ; human mammary epithelial cells ; telomerase
    Vědní obor RIVEB - Genetika a molekulární biologie
    Obor OECDCell biology
    Institucionální podporaBC-A - RVO:60077344
    UT WOS000348313100015
    DOI10.4161/15384101.2014.954456
    AnotaceTelomerase reactivation and immortalization are critical for human carcinoma progression. However, little is known about the mechanisms controlling this crucial step, due in part to the paucity of experimentally tractable model systems that can examine human epithelial cell immortalization as it might occur in vivo. We achieved efficient non-clonal immortalization of normal human mammary epithelial cells (HMEC) by directly targeting the 2 main senescence barriers encountered by cultured HMEC. The stress-associated stasis barrier was bypassed using shRNA to p16(INK4), replicative senescence due to critically shortened telomeres was bypassed in post-stasis HMEC by c-MYC transduction. Thus, 2 pathologically relevant oncogenic agents are sufficient to immortally transform normal HMEC. The resultant non-clonal immortalized lines exhibited normal karyotypes. Most human carcinomas contain genomically unstable cells, with widespread instability first observed in vivo in pre-malignant stages, in vitro, instability is seen as finite cells with critically shortened telomeres approach replicative senescence. Our results support our hypotheses that: (1) telomere-dysfunction induced genomic instability in pre-malignant finite cells may generate the errors required for telomerase reactivation and immortalization, as well as many additional passenger errors carried forward into resulting carcinomas, (2) genomic instability during cancer progression is needed to generate errors that overcome tumor suppressive barriers, but not required per se, bypassing the senescence barriers by direct targeting eliminated a need for genomic errors to generate immortalization. Achieving efficient HMEC immortalization, in the absence of passenger genomic errors, should facilitate examination of telomerase regulation during human carcinoma progression, and exploration of agents that could prevent immortalization.
    PracovištěBiologické centrum (od r. 2006)
    KontaktDana Hypšová, eje@eje.cz, Tel.: 387 775 214
    Rok sběru2018
Počet záznamů: 1  

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