DNA-dependent conversion of Oct-1 and Oct-2 into transcriptional repressors by Groucho/TLE

Malin, Stephen; Linderson, Ylva; Almqvist, Jenny; Ernberg, Ingemar; Tallone, Tiziano; Pettersson, Sven

doi:10.1093/nar/gki744

Cited by 15 publications

(19 citation statements)

References 20 publications

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“…Previous studies have shown that transcription can be repressed directly by prevention of binding of activators to DNA or by interaction with the basal transcriptional machinery. This results in at least two, possibly coordinated, processes that involve inhibition of the RNA polymerase II complex and chromatin remodeling, respectively (1,5,7,42,57). In the in vitro system, a complex of TLE2, RTA, and RRE was observed.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that TLEs are broadly expressed nuclear factors that lack intrinsic DNAbinding activity and interact with a variety of DNA-binding proteins. In invertebrates and vertebrates, Groucho/TLE family members have been shown to interact with multiple transcription factors, such as Tcf/HMG box transcription factors, Runt domain proteins, HES proteins, Hesx1, NF-B, PRDI-BF1, PU.1, HNF3b, Hex, Oct-1/Oct-2, and the androgen receptor (AR) (3,25,42,44,54,59,66,78). By recruitment of specific gene-regulatory sequences, Groucho/TLE can downregulate the expression of target genes of transcriptional activators, enhance the transcriptional repression effect of transcriptional repressors, or convert transcriptional activators into repressors (43,57).…”

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confidence: 99%

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Cellular Corepressor TLE2 Inhibits Replication-and-Transcription- Activator-Mediated Transactivation and Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Liu

Liang

et al. 2010

J Virol

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Replication and transcription activator (RTA) encoded by open reading frame 50 (ORF50) of Kaposi's sarcoma-associated herpesvirus (KSHV) is essential and sufficient to initiate lytic reactivation. RTA activates its target genes through direct binding with high affinity to its responsive elements or by interaction with cellular factors, such as RBP-J, Ap-1, C/EBP-␣, and Oct-1. In this study, we identified transducin-like enhancer of split 2 (TLE2) as a novel RTA binding protein by using yeast two-hybrid screening of a human spleen cDNA library. The interaction between TLE2 and RTA was confirmed by glutathione S-transferase (GST) binding and coimmunoprecipitation assays. Immunofluorescence analysis showed that TLE2 and RTA were colocalized in the same nuclear compartment in KSHV-infected cells. This interaction recruited TLE2 to RTA bound to its recognition sites on DNA and repressed RTA auto-activation and transactivation activity. Moreover, TLE2 also inhibited the induction of lytic replication and virion production driven by RTA. We further showed that the Q (Gln-rich), SP (Ser-Pro-rich), and WDR (Trp-Asp repeat) domains of TLE2 and the Pro-rich domain of RTA were essential for this interaction. RBP-J has been shown previously to bind to the same Pro-rich domain of RTA, and this binding can be subject to competition by TLE2. In addition, TLE2 can form a complex with RTA to access the cognate DNA sequence of the RTA-responsive element at different promoters. Intriguingly, the transcription level of TLE2 could be upregulated by RTA during the lytic reactivation process. In conclusion, we identified a new RTA binding protein, TLE2, and demonstrated that TLE2 inhibited replication and transactivation mediated by RTA. This provides another potentially important mechanism for maintenance of KSHV viral latency through interaction with a host protein.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cellular Corepressor TLE2 Inhibits Replication-and-Transcription- Activator-Mediated Transactivation and Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Liu

Liang

et al. 2010

J Virol

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“…However, in this report, we demonstrate that a mutant Grg4 protein, in which the GP-domain has been deleted, remains capable of repressing Otx2-induced transcription as efficiently as wild-type Grg4. This suggests that, as in the case of Grg4-mediated repression of Pax2 and Oct-2 activation (61,62), repression occurs via a HDAC-independent mechanism. In the case of Pax2, phosphorylation of Pax2 by c-Jun N-terminal kinase is blocked by association with Grg4, decreasing the transcriptional activity of Pax2.…”

Section: Discussionmentioning

confidence: 93%

Otx2 Induction of the Gonadotropin-releasing Hormone Promoter Is Modulated by Direct Interactions with Grg Co-repressors

Larder

Mellon

2009

Journal of Biological Chemistry

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Hormonal communication between the hypothalamus, pituitary, and gonads orchestrates the development and regulation of mammalian reproductive function. In mice, gonadotropin-releasing hormone (GnRH) expression is limited to ϳ1000 neurons that originate in the olfactory placode then migrate to specific positions scattered throughout the hypothalamus. Coordination of the hypothalamic-pituitary-gonadal axis is dependent upon correct migration of GnRH neurons into the hypothalamus followed by the appropriate synthesis and pulsatile secretion of GnRH. Defects in any one of these processes can cause infertility. Recently, substantial progress has been made in identifying transcription factors, and their cofactors, that regulate not only adult expression of GnRH, but also the maturation of GnRH neurons. Here, we show that expression of Otx2, a homeodomain protein required for the formation of the forebrain, is dramatically up-regulated during GnRH neuronal maturation and that overexpression of Otx2 increases GnRH promoter activity in GnRH neuronal cell lines. Furthermore, Otx2 transcriptional activity is modulated by Grg4, a member of the Groucho-related-gene (Grg) family. Using mutational analysis, we show that a WRPW peptide motif within the Otx2 protein is required for physical interaction between Otx2 and Grg4. Without this physical interaction, Grg4 cannot repress Otx2-dependent activation of GnRH gene transcription. Taken together, these data show that Otx2 is important for GnRH expression and that direct interaction between Otx2 and Grg co-repressors regulates GnRH gene expression in hypothalamic neurons.

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“…Interestingly, Oct-1 also interacts directly with herpes simplex virus (HSV)-and varicella-zoster virus (VZV)-encoded tegument proteins (VP16 and ORF10, respectively), and this interaction is required for the efficient activation of the HSV and VZV immediate-early promoters (34,45,46,58,93). While Oct-1 and the related POU domain transcription factor, Oct-2, have been previously suggested to play a role in regulating the type of EBV latency (3,55,90), neither protein has been shown to play a role in EBV lytic reactivation.…”

Section: Epstein-barr Virus (Ebv) or Human Herpesvirus 4 (Hhv4)mentioning

confidence: 99%

Cellular Transcription Factor Oct-1 Interacts with the Epstein-Barr Virus BRLF1 Protein To Promote Disruption of Viral Latency

Robinson

Kwek

Hagemeier

et al. 2011

J Virol

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The Epstein-Barr virus (EBV) latent-to-lytic switch is an essential part of the viral life cycle, but the cellular factors that promote viral reactivation are not well defined. In this report, we demonstrate that the cellular transcription factor Oct-1 cooperates with the EBV immediate-early protein BRLF1 (R, Rta) to induce lytic viral reactivation. We show that cotransfected Oct-1 enhances the ability of BRLF1 to activate lytic gene expression in 293 cells stably infected with a BRLF1-defective EBV mutant (BRLF1-stop) and that Oct-1 increases BRLF1-mediated activation of lytic EBV promoters in reporter gene assays. We find that Oct-1 interacts directly with BRLF1 in vitro and that a mutant BRLF1 protein (the M140A mutant) attenuated for the ability to interact with Oct-1 in vitro is also resistant to Oct-1-mediated transcriptional enhancement in 293 BRLF1-stop cells. Furthermore, we show that cotransfected Oct-1 augments BRLF1 binding to a variety of lytic EBV promoters in chromatin immunoprecipitation (ChIP) assays (including the BZLF1, BMRF1, and SM promoters) and that BRLF1 tethers Oct-1 to lytic EBV promoters. In addition, we demonstrate that an Oct-1 mutant defective in DNA binding (the S335D mutant) still retains the ability to enhance BRLF1 transcriptional effects. Finally, we show that knockdown of endogenous Oct-1 expression reduces the level of constitutive lytic EBV gene expression in both EBV-positive B-cell and EBV-positive epithelial cell lines. These results suggest that Oct-1 acts as a positive regulator of EBV lytic gene expression and that this effect is at least partially mediated through its interaction with the viral protein BRLF1. Epstein-Barr virus (EBV), or human herpesvirus 4 (HHV4), is a double-stranded DNA gammaherpesvirus which infects approximately 90% of the world's population (66). It causes a relatively mild primary disease if acquired early in life and infectious mononucleosis if acquired after adolescence. EBV is also associated with several B-cell and epithelial cell cancers, including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma (NPC), and gastric carcinoma (66, 101).EBV infection persists for the life of the host as a chronic asymptomatic infection by establishing latency in memory B cells (77). However, to be transmitted from host to host, and from cell to cell, the virus periodically reactivates from latency and converts to the lytic form of replication (66). Reactivation of lytic EBV infection in host cells is controlled at the level of the BZLF1 (Z, Zta, ZEBRA, EB1) and BRLF1 (R, Rta) viral promoters, as well as the activity of the BZLF1 and BRLF1 gene products (24,42,95). The BZLF1 and BRLF1 genes encode transcription factors that cooperatively turn on the expression of the early lytic viral genes involved in lytic viral replication (2,9,16,17,23,24,26,29,31,41,50,62,68), and the overexpression of either BZLF1 or BRLF1 is sufficient to induce lytic gene expression in many latently infected cell lines (13-15, 63, 83, 96). Since the combination of both BZL...

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DNA-dependent conversion of Oct-1 and Oct-2 into transcriptional repressors by Groucho/TLE

Cited by 15 publications

References 20 publications

Cellular Corepressor TLE2 Inhibits Replication-and-Transcription- Activator-Mediated Transactivation and Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Cellular Corepressor TLE2 Inhibits Replication-and-Transcription- Activator-Mediated Transactivation and Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Otx2 Induction of the Gonadotropin-releasing Hormone Promoter Is Modulated by Direct Interactions with Grg Co-repressors

Cellular Transcription Factor Oct-1 Interacts with the Epstein-Barr Virus BRLF1 Protein To Promote Disruption of Viral Latency

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