14-3-3 Proteins Modulate the ETS Transcription Factor ETV1 in Prostate Cancer

Oh, Sangphil; Shin, Sook; Lightfoot, Stan; Janknecht, Ralf

doi:10.1158/0008-5472.can-13-0578

Cited by 30 publications

(38 citation statements)

References 47 publications

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“…YWHAE is among the 14-3-3 proteins that regulate the ETV1 transcription factor in PCa [26]. TRFC was shown originally to be significantly induced in DU145 cells [27], CORO1C/coronin was found to be induced in androgen-insensitive PCa [28] and S100A16 appears to be upregulated only in metastatic tumor cells [29].…”

Section: Resultsmentioning

confidence: 99%

Analysis of Argonaute Complex Bound mRNAs in DU145 Prostate Carcinoma Cells Reveals New miRNA Target Genes

Szczyrba

Jung

Beitzinger³

et al. 2017

Prostate Cancer

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Posttranscriptional gene regulation by microRNAs (miRNAs) contributes to the induction and maintenance of prostate carcinoma (PCa). To identify mRNAs enriched or removed from Ago2-containing RISC complexes, these complexes were immunoprecipitated from normal prostate fibroblasts (PNFs) and the PCa line DU145 and the bound mRNAs were quantified by microarray. The analysis of Ago complexes derived from PNFs or DU145 confirmed the enrichment or depletion of a variety of mRNAs already known from the literature to be deregulated. Novel potential targets were analyzed by luciferase assays with miRNAs known to be deregulated in PCa. We demonstrate that the mRNAs of the death effector domain-containing protein (DEDD), the tumor necrosis factor receptor superfamily, member 10b protein (TNFRSF10B), the tumor protein p53 inducible nuclear protein 1 (TP53INP1), and the secreted protein, acidic, cysteine-rich (SPARC; osteonectin) are regulated by miRNAs miR-148a, miR-20a, miR-24, and miR-29a/b, respectively. Therefore, these miRNAs represent potential targets for therapy. Surprisingly, overexpression of miR-24 induced focus formation and proliferation of DU145 cells, while miR-29b reduced proliferation. The study confirms genes deregulated in PCa by virtue of their presence/absence in the Ago2-complex. In conjunction with the already published miRNA profiles of PCa, the data can be used to identify miRNA-regulated mRNAs.

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Section: Resultsmentioning

confidence: 99%

Analysis of Argonaute Complex Bound mRNAs in DU145 Prostate Carcinoma Cells Reveals New miRNA Target Genes

Szczyrba

Jung

Beitzinger³

et al. 2017

Prostate Cancer

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“…We found that 3 isoforms are bound strongly: 14-3-3, which is consistent with our previous studies (23), plus 14-3-3ε and 14-3-3. These isoforms all have important roles to play in diverse aspects of cellular homeostasis (27)(28)(29), and it is now imperative to ascertain how E6 interaction with these isoforms affects E6 activity and 14-3-3 functions. These findings have also facilitated a series of studies to assess the ability of the other high-risk HPV E6 oncoproteins to interact with 14-3-3 in a phosphorylation-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, we recently showed that this phosphorylated E6 could instead interact with 14-3-3 (23), a phospho-serine/threonine binding protein (26). There are seven different isoforms of 14-3-3, which play diverse roles in the regulation of cellular homeostasis, many of these functions being relevant for cancer development (27)(28)(29). This suggests that the E6 PBM is actually bifunctional, mediating interaction with either PDZ domain-containing substrates or 14-3-3 family members, depending upon the E6 phosphorylation status.…”

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confidence: 99%

Cancer-Causing Human Papillomavirus E6 Proteins Display Major Differences in the Phospho-Regulation of Their PDZ Interactions

Boon

Tomaić

Thomas

et al. 2015

J Virol

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Previous studies have shown that the cancer-causing high-risk human papillomavirus (HPV) E6 oncoproteins have PDZ binding potential, an activity which is important for their ability to support the viral life cycle and to cooperate in the induction of malignancy. However, PDZ interactions are not constitutive, and they can be negatively regulated by phosphorylation within the E6 PDZ binding motif (PBM). In this study, we have investigated the differential regulation of the HPV E6 PBMs from diverse highrisk HPV types. We show that, depending on the HPV type, PDZ binding activity can be regulated by phosphorylation with protein kinase A (PKA) or AKT, which, in turn, inhibits PDZ recognition. Such regulation is highly conserved between E6 proteins derived from HPV-16, HPV-18, and HPV-58 while being somewhat weaker or absent from other types such as HPV-31, HPV-33, and HPV-51. In the case of HPV31, PKA phosphorylation occurs within the core of the E6 protein and has no effect on PDZ interactions, and this demonstrates a surprising degree of heterogeneity among the different high-risk HPV E6 oncoproteins in how they are regulated by different cellular signaling pathways. IMPORTANCEThis study demonstrated that the cancer-causing HPV E6 oncoproteins are all subject to posttranslational modification of their extreme C-terminal PDZ binding motifs through phosphorylation. However, the identities of the kinase are not the same for all HPV types. This demonstrates a very important divergence between these HPVs, and it suggests that changes in cell signaling pathways have different consequences for different high-risk virus infections and their associated malignancies.H uman papillomaviruses (HPVs) are the causative agents of cervical cancer, which remains a leading cause of death in women throughout the world. Over 120 different HPV types have been identified, 12 of which are defined as cancer causing (1, 2). Of these, HPV-16 and HPV-18 are the most important, accounting for approximately 70% of cervical cancers. The remaining cancers are caused by other high-risk (HR) HPV types, which include 2). HPVinduced carcinogenesis arises from the combined activity of the two major viral oncoproteins E6 and E7, which, by deregulating multiple cellular pathways, including cell cycle control and apoptosis, ultimately induce cell immortalization and, eventually, malignancy (3, 4).A unique characteristic of the HR HPV E6 oncoproteins is the presence of a class I PDZ (PSD-95/Dlg/ZO-1) binding motif (PBM) at the extreme carboxy terminus, which is absent in the low-risk (LR) non-cancer-causing HPV E6 proteins (5, 6). This region of E6 allows it to interact with a number of cellular PDZ domain-containing proteins, many of which are involved in the regulation of cell junctional integrity and cell signaling pathways (reviewed in reference 7). The first such targets to be identified were the cell polarity regulators Discs Large (hDlg1) (5,7,8) and Scribble (hScrib) (9), which were shown to be degraded by HPV-16 and HPV-18 E6 in a protea...

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“…Numerous erythroblastosis virus E26 transformation-specific (ETS) transcription factors contribute to the development of cancers (Oh, 2013; Reddy, 1991; Shin, 2013). ETV1, ETV2, ETV3, ETV4, Fli-1, and ERG are examples of these factors (Fang, 2014; Rao, 1987; Reddy, 1989; Spans, 2013).…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of <I>β</I>-Catenin Signaling Pathway Inactivation in ETV1-Positive Prostate Cancers

Morsalin

Yang

Fang

et al. 2015

j pharmaceut sci pharmacol

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In the United States of America, prostate cancer is the second most common age-related cancer among men. African-American men have the highest incidence of, and mortality rate from this disease in the United States. According to the American Cancer Society, 29% of all cancer cases and 9% of all cancer deaths are a result of prostate cancer. Individuals who are at highest risk include African-American men, men over 60 years of age, and those with a family history of the disease. African-Americans also have twice the risk of developing prostate cancer as compared to Caucasians. Erythroblastosis virus E26 transformation-specific (ETS) factors play an important role in human cancers. ETS Variant 1 (ETV1), an ETS factor, is notable for its association in prostate cancers, where truncated ETV1 (dETV1) or its full length counterpart is overexpressed in approximately 10% of the prostate cancer patients. Prostate cancer tumorigenesis may be initiated by deregulation of the Wnt/β-catenin pathway. Mutations that stabilize β-catenin were shown to contribute to the loss of cell-growth control in tumorigenesis. We hypothesized that ETV1’s interaction with components of the Wnt/β-catenin pathway may alter β-catenin’s interaction with downstream tumor-suppressor genes, which are critical in regulating apoptosis and cell-growth properties of prostate cells. Our results demonstrate for the first time that ETV1 alters β-catenin activity by activating kinases that regulate Wnt/β-catenin activity through post-translational modification in prostate cancer cells. We further demonstrate that therapeutic agents such as PD98059, that reverse effect of ETV1 on Wnt/β-catenin signaling pathway, can be used to target ETV1-positive prostate cancer cells. These therapeutic agents could have a profound impact on prevention and treatment of prostate cancer which may help to reduce health disparity seen in minority patients. Understanding the role of ETV1 in Wnt/β-catenin pathway will also allow us to develop better diagnostic tools, which can be used as a biomarker for ETV1-positive prostate cancers.

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14-3-3 Proteins Modulate the ETS Transcription Factor ETV1 in Prostate Cancer

Cited by 30 publications

References 47 publications

Analysis of Argonaute Complex Bound mRNAs in DU145 Prostate Carcinoma Cells Reveals New miRNA Target Genes

Analysis of Argonaute Complex Bound mRNAs in DU145 Prostate Carcinoma Cells Reveals New miRNA Target Genes

Cancer-Causing Human Papillomavirus E6 Proteins Display Major Differences in the Phospho-Regulation of Their PDZ Interactions

Molecular Mechanism of <I>β</I>-Catenin Signaling Pathway Inactivation in ETV1-Positive Prostate Cancers

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