Sladjana Gagrica

Publications (3)22.42 Total impact

• Article: Contrasting behavior of the p18INK4c and p16INK4a tumor suppressors in both replicative and oncogene-induced senescence.

  Sladjana Gagrica, Sharon Brookes, Emma Anderton, Janice Rowe, Gordon Peters
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  ABSTRACT: The cyclin-dependent kinase (CDK) inhibitors, p18(INK4c) and p16(INK4a), both have the credentials of tumor suppressors in human cancers and mouse models. For p16(INK4a), the underlying rationale is its role in senescence, but the selective force for inactivation of p18(INK4c) in incipient cancer cells is less clear. Here, we show that in human fibroblasts undergoing replicative or oncogene-induced senescence, there is a marked decline in the levels of p18(INK4c) protein and RNA, which mirrors the accumulation of p16(INK4a). Downregulation of INK4c is not dependent on p16(INK4a), and RAS can promote the loss of INK4c without cell-cycle arrest. Downregulation of p18(INK4c) correlates with reduced expression of menin and E2F1 but is unaffected by acute cell-cycle arrest or inactivation of the retinoblastoma protein (pRb). Collectively, our data question the idea that p18(INK4c) acts as a backup for loss of p16(INK4a) and suggest that the apparent activation of p18(INK4c) in some settings represents delayed senescence rather than increased expression. We propose that the contrasting behavior of the two very similar INK4 proteins could reflect their respective roles in senescence versus differentiation.
  Cancer Research 11/2011; 72(1):165-75. · 7.86 Impact Factor
• Source

  Available from: uni-wuerzburg.de

  Article: LINC, a human complex that is related to pRB-containing complexes in invertebrates regulates the expression of G2/M genes.

  Fabienne Schmit, Michael Korenjak, Mirijam Mannefeld, Kathrin Schmitt, Claudia Franke, Björn von Eyss, Sladjana Gagrica, Frank Hänel, Alexander Brehm, Stefan Gaubatz
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  ABSTRACT: Here we report the identification of the LIN complex (LINC), a human multiprotein complex that is required for transcriptional activation of G2/M genes. LINC is related to the recently identified dREAM and DRM complexes of Drosophila and C. elegans that contain homologs of the mammalian retinoblastoma tumor suppressor protein. The LINC core complex consists of at least five subunits including the chromatin-associated LIN-9 and RbAp48 proteins. LINC dynamically associates with pocket proteins, E2F and B-MYB during the cell cycle. In quiescent cells, LINC binds to p130 and E2F4. During cell cycle entry, E2F4 and p130 dissociate and LINC switches to B-MYB and p107. Chromatin Immunoprecipitation experiments demonstrate that LINC associates with a large number of E2F-regulated promoters in quiescent cells. However, RNAi experiments reveal that LINC is not required for repression. In S-phase, LINC selectively binds to the promoters of G2/M genes whose products are required for mitosis and plays an important role in their cell cycle dependent activation.
  Cell cycle (Georgetown, Tex.) 09/2007; 6(15):1903-13. · 5.36 Impact Factor
• Source

  Available from: ncbi.nlm.nih.gov

  Article: Inhibition of oncogenic transformation by mammalian Lin-9, a pRB-associated protein.

  Sladjana Gagrica, Stefanie Hauser, Ingrid Kolfschoten, Lisa Osterloh, Reuven Agami, Stefan Gaubatz
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  ABSTRACT: Genetic studies in Caenorhabditis elegans identified lin-9 to function together with the retinoblastoma homologue lin-35 in vulva differentiation. We have now identified a human homologue of Lin-9 (hLin-9) and provide evidence about its function in the mammalian pRB pathway. hLin-9 binds to pRB and cooperates with pRB in flat cell formation in Saos-2 cells. In addition, hLin-9 synergized with pRB and Cbfal to transactivate an osteoblast-specific reporter gene. In contrast, hLin-9 was not involved in pRB-mediated inhibition of cell cycle progression or repression of E2F-dependent transactivation. Consistent with these data, hLin-9 was able to associate with partially penetrant pRB mutants that do not bind to E2F, but retain the ability to activate transcription and to promote differentiation. hLin-9 can also inhibit oncogenic transformation, dependent on the presence of a functional pRB protein. RNAi-mediated knockdown of Lin-9 can substitute for the loss of pRB in transformation of human primary fibroblasts. These data suggest that hLin-9 has tumor-suppressing activities and that the ability of hLin-9 to inhibit transformation is mediated through its association with pRB.
  The EMBO Journal 11/2004; 23(23):4627-38. · 9.20 Impact Factor