Loss of LIN9, a member of the DREAM complex, cooperates with SV40 large T antigen to induce genomic instability and anchorage-independent growth

Hauser, Stefanie; Ulrich, Tanja; Wurster, Sebastian; Schmitt, Kathrin; Reichert, Nina; Gaubatz, Stefan

doi:10.1038/onc.2011.364

Cited by 19 publications

(19 citation statements)

References 28 publications

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“…The RB pocket protein-E2F pathway is a target for several oncoproteins originating from DNA viruses with HPV E7, adenovirus early-region 1A (E1A) and polyomavirus large T-antigens as prominent examples (29,99). Consistent with this notion, also SV40 large T was recently reported to impair DREAM function (100,101). …”

Section: Discussionsupporting

confidence: 71%

Polo-like kinase 4 transcription is activated via CRE and NRF1 elements, repressed by DREAM through CDE/CHR sites and deregulated by HPV E7 protein

Fischer

Quaas

Wintsche

et al. 2013

Nucleic Acids Research

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Infection by oncogenic viruses is a frequent cause for tumor formation as observed in cervical cancer. Viral oncoproteins cause inactivation of p53 function and false transcriptional regulation of central cell cycle genes. Here we analyze the regulation of Plk4, serving as an example of many cell cycle- and p53-regulated genes. Cell cycle genes are often repressed via CDE and CHR elements in their promoters and activated by NF-Y binding to CCAAT-boxes. In contrast, general activation of Plk4 depends on NRF1 and CRE sites. Bioinformatic analyses imply that NRF1 and CRE are central elements of the transcriptional network controlling cell cycle genes. We identify CDE and CHR sites in the Plk4 promoter, which are necessary for binding of the DREAM (DP, RB-like, E2F4 and MuvB) complex and for mediating repression in G0/G1. When cells progress to G2 and mitosis, DREAM is replaced by the MMB (Myb-MuvB) complex that only requires the CHR element for binding. Plk4 expression is downregulated by the p53-p21WAF1/CIP1-DREAM signaling pathway through the CDE and CHR sites. Cell cycle- and p53-dependent repression is abrogated by HPV E7 oncoprotein. Together with genome-wide analyses our results imply that many cell cycle genes upregulated in tumors by viral infection are bound by DREAM through CDE/CHR sites.

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Section: Discussionsupporting

confidence: 71%

Polo-like kinase 4 transcription is activated via CRE and NRF1 elements, repressed by DREAM through CDE/CHR sites and deregulated by HPV E7 protein

Fischer

Quaas

Wintsche

et al. 2013

Nucleic Acids Research

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“…Several other viral oncoproteins target the pocket proteins through LxCxE motifs, including adenovirus early-region 1A (E1A) and large T antigens of several polyomaviruses, such as SV40, JCV and BKV 58 . Consistent with this notion, also SV40 large T was reported to impair DREAM function 59, 60 .…”

Section: Discussionsupporting

confidence: 61%

Human papilloma virus E7 oncoprotein abrogates the p53-p21-DREAM pathway

Fischer

Uxa

Stanko

et al. 2017

Sci Rep

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High risk human papilloma viruses cause several types of cancer. The HPV oncoproteins E6 and E7 are essential for oncogenic cell transformation. E6 mediates the degradation of the tumor suppressor p53, and E7 can form complexes with the retinoblastoma pRB tumor suppressor. Recently, it has been shown that HPV E7 can also interfere with the function of the DREAM transcriptional repressor complex. Disruption of DREAM-dependent transcriptional repression leads to untimely early expression of central cell cycle regulators. The p53-p21-DREAM pathway represents one important means of cell cycle checkpoint activation by p53. By activating this pathway, p53 can downregulate transcription of genes controlled by DREAM. Here, we present a genome-wide ranked list of genes deregulated by HPV E7 expression and relate it to datasets of cell cycle genes and DREAM targets. We find that DREAM targets are generally deregulated after E7 expression. Furthermore, our analysis shows that p53-dependent downregulation of DREAM targets is abrogated when HPV E7 is expressed. Thus, p53 checkpoint control is impaired by HPV E7 independently of E6. In summary, our analysis reveals that disruption of DREAM through the HPV E7 oncoprotein upregulates most, if not all, cell cycle genes and impairs p53’s control of cell cycle checkpoints.

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“…Expression of genes encoding these proteins as well as eight additional mitotic kinesins (36) were downregulated following BETi treatment. Prior studies have shown that loss of LIN9 expression produces polyploid cells with aberrant nuclei and induces senescence (49, 55). Thus, data presented herein not only confirm the impact of LIN9 on mitosis, but also implicate LIN9 as an intermediate between BET proteins and effective mitosis in TNBC.…”

Section: Discussionmentioning

confidence: 99%

Mitotic Vulnerability in Triple-Negative Breast Cancer Associated with LIN9 Is Targetable with BET Inhibitors

et al. 2017

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Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of Bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe. Mechanistically, the mitosis regulator LIN9 was a direct target of BET proteins that mediated the effects of BET proteins on mitosis in TNBC. While BETi have been proposed to function by dismantling super-enhancers (SE), the LIN9 gene lacks a SE but was amplified or overexpressed in the majority of TNBCs. In addition, its mRNA expression predicted poor outcome across breast cancer subtypes. Together, these results provide a mechanism for cancer selectivity of BETi that extends beyond modulation of SE-associated genes and suggest that cancers dependent upon LIN9 overexpression may be particularly vulnerable to BETi.

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Loss of LIN9, a member of the DREAM complex, cooperates with SV40 large T antigen to induce genomic instability and anchorage-independent growth

Cited by 19 publications

References 28 publications

Polo-like kinase 4 transcription is activated via CRE and NRF1 elements, repressed by DREAM through CDE/CHR sites and deregulated by HPV E7 protein

Polo-like kinase 4 transcription is activated via CRE and NRF1 elements, repressed by DREAM through CDE/CHR sites and deregulated by HPV E7 protein

Human papilloma virus E7 oncoprotein abrogates the p53-p21-DREAM pathway

Mitotic Vulnerability in Triple-Negative Breast Cancer Associated with LIN9 Is Targetable with BET Inhibitors

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