ZIP: A novel transcription repressor, represses EGFR oncogene and suppresses breast carcinogenesis

Department of Biochemistry and Molecular Biology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Health Science Center, Beijing, China.
The EMBO Journal (Impact Factor: 10.43). 08/2009; 28(18):2763-76. DOI: 10.1038/emboj.2009.211
Source: PubMed


Despite the importance of epidermal growth factor receptor (EGFR) in animal development and malignant transformation, surprisingly little is known about the regulation of its expression. Here, we report a novel zinc finger and G-patch domain-containing protein, ZIP. We demonstrated that ZIP acts as a transcription repressor through the recruitment of the nucleosome remodelling and deacetylase complex. Transcriptional target analysis revealed that ZIP regulates several cellular signalling pathways including EGFR pathways that are critically involved in cell proliferation, survival, and migration. We showed that ZIP inhibits cell proliferation and suppresses breast carcinogenesis, and that ZIP depletion leads to a drastic tumour growth in vivo. We found that ZIP is downregulated in breast carcinomas and that its level of expression is negatively correlated with that of EGFR. Our data indicate that ZIP is a novel transcription repressor and a potential tumour suppressor. These findings may shed new light on the EGFR-related breast carcinogenesis and might offer a potential new target for breast cancer therapy.

Download full-text


Available from: Bin Gui,
  • Source
    • "Expression of Vpr did not significantly modify the cellular repartition of Cul4ADDB1 (Figure 1C) or the localization of exogenous ZIP or sZIP (data not shown). Next, we wondered whether Vpr was able to recruit the NuRD complex, as ZIP or sZIP does [32,33]. Vpr interacted with RbAp46, as well as with HAT1, confirming the data from Jäger et al., obtained from a global analysis of HIV interacting cellular partners [38] (Figure 1E). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Vpr protein from type 1 and type 2 Human Immunodeficiency Viruses (HIV-1 and HIV-2) is thought to inactivate several host proteins through the hijacking of the DCAF1 adaptor of the Cul4A ubiquitin ligase. Here, we identified two transcriptional regulators, ZIP and sZIP, as Vpr-binding proteins degraded in the presence of Vpr. ZIP and sZIP have been shown to act through the recruitment of the NuRD chromatin remodeling complex. Strikingly, chromatin is the only cellular fraction where Vpr is present together with Cul4A ubiquitin ligase subunits. Components of the NuRD complex and exogenous ZIP and sZIP were also associated with this fraction. Several lines of evidence indicate that Vpr induces ZIP and sZIP degradation by hijacking DCAF1: (i) Vpr induced a drastic decrease of exogenously expressed ZIP and sZIP in a dose-dependent manner, (ii) this decrease relied on the proteasome activity, (iii) ZIP or sZIP degradation was impaired in the presence of a DCAF1-binding deficient Vpr mutant or when DCAF1 expression was silenced. Vpr-mediated ZIP and sZIP degradation did not correlate with the growth-related Vpr activities, namely G2 arrest and G2 arrest-independent cytotoxicity. Nonetheless, infection with HIV-1 viruses expressing Vpr led to the degradation of the two proteins. Altogether our results highlight the existence of two host transcription factors inactivated by Vpr. The role of Vpr-mediated ZIP and sZIP degradation in the HIV-1 replication cycle remains to be deciphered.
    PLoS ONE 10/2013; 8(10):e77320. DOI:10.1371/journal.pone.0077320 · 3.23 Impact Factor
  • Source
    • "All the differentially expressed genes were analyzed using a free web-based Molecular Annotation System 2.0 (MAS 2.0, [27, 28]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We aimed to compare bone-marrow-derived mesenchymal stem cells (BMMSCs) between systemic lupus erythematosus (SLE) and normal controls by means of cDNA microarray, immunohistochemistry, immunofluorescence, and immunoblotting. Our results showed there were a total of 1, 905 genes which were differentially expressed by BMMSCs derived from SLE patients, of which, 652 genes were upregulated and 1, 253 were downregulated. Gene ontology (GO) analysis showed that the majority of these genes were related to cell cycle and protein binding. Pathway analysis exhibited that differentially regulated signal pathways involved actin cytoskeleton, focal adhesion, tight junction, and TGF-β pathway. The high protein level of BMP-5 and low expression of Id-1 indicated that there might be dysregulation in BMP/TGF-β signaling pathway. The expression of Id-1 in SLE BMMSCs was reversely correlated with serum TNF-α levels. The protein level of cyclin E decreased in the cell cycling regulation pathway. Moreover, the MAPK signaling pathway was activated in BMMSCs from SLE patients via phosphorylation of ERK1/2 and SAPK/JNK. The actin distribution pattern of BMMSCs from SLE patients was also found disordered. Our results suggested that there were distinguished differences of BMMSCs between SLE patients and normal controls.
    Clinical and Developmental Immunology 08/2012; 2012(1):826182. DOI:10.1155/2012/826182 · 2.93 Impact Factor
  • Source
    • "The histone demethylase JARID1B is involved in the proliferation of cancer cells through the E2F/reti- noblastoma pathway [27]. The retinoblastoma-binding proteins p48 (RBAP48) and p46 (RBAP46) are present in protein complexes involved in histone acetylation and chromatin assembly as well as is a part of co-repressor complexes, which is an integral component of transcriptional silencing, and seems to be involved in transcriptional repression of E2F-responsive genes [28]. Moreover , RBAP46 and RBAP48 interact with estrogen receptor alpha at endogenous, estrogen-responsive genes Copyright © 2012 SciRes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The expression of retinoblastoma and several retino-blastoma-related genes was studied in glioma cell line U87 and its subline with knockdown of ERN1 (endo-plasmic reticulum—nuclei-1), the main endoplasmic reticulum stress sensing and signaling enzyme. It was shown that a blockade of the ERN1 enzyme function increases the expression levels of retinoblastoma, re-tinoblastoma-like 1 and most retinoblastoma related genes: EID1, JARID1B, E2F1, E2F3, RBAP48 and CTIP, does not change RNF40 and RBAP46 and de-creases KDM5A. We have also demonstrated that hy-poxia reduces the expression levels of retinoblastoma, EID1, and E2F1 in ERN1-deficient glioma cells only. At the same time, the expression levels of retinoblas-toma-like 1, E2F3, RBAP46, RBAP48 and CTIP de-crease, while JARID1B and RBBP2 increase in both types of cells in hypoxic conditions, but the expression is much stronger in cells with suppressed function of ERN1. The expression level of JARID1B and KDM-5A mRNA is also enhanced in glutamine deprivation condition in both tested cell types, moreover, this ef-fect is amplified by the blockade of the ERN1 enzyme function. The expression levels of retinoblastoma, EID1, RBAP48, and E2F3 are decreased in glutamine deprivation condition only in ERN1-deficient glioma cells, but RBL1, CTIP, RBAP46, and E2F1—in both tested cell types with more significant effect in ERN1-deficient cells. Glucose deprivation condition leads to a decrease of expression levels of retinoblastoma, RBL1, E2F3, RBAP46, and RBAP48 in both used cell types and of EID1 and E2F1 only in glioma cells with suppressed function of signaling enzyme ERN1. Thus, expression levels of retinoblastoma and most retino-blastoma-related genes are increased under a block-ade of ERN1 enzyme function and significantly changed in hypoxia, glucose or glutamine deprivation condi-tions both in control U87 cells and ERN1-deficient cells, but inhibition of the unfolded protein response sensor ERN1 predominantly enhances these effects. Moreover, it is possible that the induction of the ex-pression of retinoblastoma and most retinoblastoma-related genes after knockdown of ERN1 plays an im-portant role in suppression of glioma proliferation.
    American Journal of Molecular Biology 01/2012; 02(01). DOI:10.4236/ajmb.2012.21003
Show more