ELL is an HIF‐1α partner that regulates and responds to hypoxia response in PC3 cells

Liu, Lingqi; Ai, Junkui; Xiao, Wuhan; Liu, June; Wang, Yujuan; Xin, Dianqi; He, Zhisong; Guo, Yinglu; Wang, Zhou

doi:10.1002/pros.21113

Cited by 12 publications

(13 citation statements)

References 32 publications

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“…In agreement with the increased incidence of mPIN lesions, the number of CD31-positive intraductal vessels as well as total microvessel density increased significantly in all lobes of the Ell2 -cko prostate as compared to wild-type control animals (Figure 4A, B, C). Since EAF and ELL proteins have overlapping functions, and both EAF2 (Xiao, et al 2009; Chen, et al 2014) and ELL (Liu, et al 2010) interact with HIF1α, we examined its expression in response to ELL2 loss. Hif1α gene expression was significantly increased in Ell2 -cko mice compared to wild-type controls (Figure 4D), while VEGF levels were not significantly different (see Figure 5).…”

Section: Resultsmentioning

confidence: 99%

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

Pascal

Masoodi

Liu

et al. 2017

Journal of Endocrinology

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Elongation factor, RNA polymerase II, 2 (ELL2) is an RNA Pol II elongation factor with functional properties similar to ELL that can interact with the prostate tumor suppressor EAF2. In the prostate, ELL2 is an androgen response gene that is up-regulated in benign prostatic hyperplasia (BPH). We recently showed that ELL2 loss could enhance prostate cancer cell proliferation and migration, and that ELL2 gene expression was down-regulated in high Gleason score prostate cancer specimens. Here, prostate-specific deletion of ELL2 in a mouse model revealed a potential role for ELL2 as a prostate tumor suppressor in vivo. Ell2 knockout mice exhibited prostatic defects including increased epithelial proliferation, vascularity and PIN lesions similar to the previously determined prostate phenotype in Eaf2 knockout mice. Microarray analysis of prostates from Ell2 knockout and wild-type mice on a C57BL/6J background at age 3 mos and qPCR validation at 17 mos of age revealed a number of differentially expressed genes associated with proliferation, cellular motility and epithelial and neural differentiation. OncoPrint analysis identified combined down-regulation or deletion in prostate adenocarcinoma cases from the Cancer Genome Atlas (TCGA) data portal. These results suggest that ELL2 and its pathway genes likely play an important role in the development and progression of prostate cancer.

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Section: Resultsmentioning

confidence: 99%

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

Pascal

Masoodi

Liu

et al. 2017

Journal of Endocrinology

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“…Plasmid Construction, Co-immunoprecipitation, and Western Blotting-The detailed procedures were described previously (22). Using RT-PCR, C. elegans ell-1 and eaf-1 ORF regions were amplified and cloned into pEGFP-C1 and pCMVMyc vectors.…”

Section: Methodsmentioning

confidence: 99%

“…To examine whether EAF2/ELL family proteins also regulate collagen gene expression in mammals, we analyzed collagen gene expression in a PC3 prostate cancer cell line stably overexpressing the human ELL gene (22). Among several collagen genes tested, the Col3A1 gene (one of the orthologs of the C. elegans dpy-3, dpy-13, and sqt-3 genes) was significantly upregulated by ELL overexpression (Fig.…”

Section: Regulation Of Cuticle Collagen Gene Expression By Eaf-1 and mentioning

confidence: 99%

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Regulation of Fertility, Survival, and Cuticle Collagen Function by the Caenorhabditis elegans eaf-1 and ell-1 Genes

Cai

Phong

Fisher

et al. 2011

Journal of Biological Chemistry

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EAF2, an androgen-regulated protein, interacts with members of the ELL (eleven-nineteen lysine-rich leukemia) transcription factor family and also acts as a tumor suppressor. Although these proteins control transcriptional elongation and perhaps modulate the effects of other transcription factors, the mechanisms of their actions remain largely unknown. To gain new insights into the biology of the EAF2 and ELL family proteins, we used Caenorhabditis elegans as a model to explore the in vivo roles of their worm orthologs. Through the use of transgenic worms, RNAi, and an eaf-1 mutant, we found that both genes are expressed in multiple cell types throughout the worm life cycle and that they play important roles in fertility, survival, and body size regulation. ELL-1 and EAF-1 likely contribute to these activities in part through modulating cuticle synthesis, given that we observed a disrupted cuticle structure in ell-1 RNAi-treated or eaf-1 mutant worms. Consistent with disruption of cuticle structure, loss of either ELL-1 or EAF-1 suppressed the rol phenotype of specific collagen mutants, possibly through the control of dpy-3, dpy-13, and sqt-3 collagen gene expression. Furthermore, we also noted the regulation of collagen expression by ELL overexpression in PC3 human prostate cancer cells. Together, these results reveal important roles for the eaf-1 and ell-1 genes in the regulation of extracellular matrix components.Androgens play a key role in prostate development, prostate cancer, and benign prostatic hyperplasia. Thus, identification and characterization of androgen-responsive genes could significantly contribute to the prevention and treatment of prostate cancer and benign prostatic hyperplasia. One such androgen-responsive gene is EAF2 (ELL-associated factor 2), which may serve as a tumor suppressor (1). The EAF2 locus exhibits frequent allelic loss in ϳ80% of advanced clinical prostate cancer specimens, and evidence for homozygous deletion also exists (1). EAF2 deficiency in mice leads to carcinogenesis in multiple tissues (2) as well as aspermatogenesis and reduced survival (3). In addition to EAF2, mammals also express EAF1, a protein that shares 58% identity and 74% similarity with EAF2. Both EAF proteins interact with the ELL family of transcription elongation factors, including ELL, ELL2, and ELL3 (4 -9). ELL has been identified in an array of species, including yeast (10), Drosophila (11), zebrafish (12), mouse (13), and human (14). This widely expressed gene is essential for embryonic development because deletion of ELL in mouse or Drosophila causes embryonic lethality (15,16). ELL also plays an important role in leukemia (8,17). Chromosomal translocation can lead to fusion of ELL with the MLL (multiple lineage leukemia) gene, and the MLL-ELL fusion protein can cause acute myeloid leukemia (8,18).The mechanisms of EAF/ELL action appear to be complex and involve multiple signaling pathways. ELL family proteins interact with RNA polymerase II and act as a transcription elongation factor (4, 19). Eisse...

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“…In addition, the targeted knockout of ELL in mice causes embryonic lethality, suggesting that ELL has a crucial role in early embryogenesis (11). ELL has been also identified as a partner of steroid receptors p53, hypoxia-inducible factor 1␣ (HIF-1␣), and EAF1/2, modulating their binding partner activity in either a positive or negative manner (12)(13)(14)(15). While multiple lines of evidence point to the importance of ELL in normal and cancerous cells, the exact mechanism of its activity remains elusive.…”

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confidence: 99%

ELL Inhibits E2F1 Transcriptional Activity by Enhancing E2F1 Deacetylation via Recruitment of Histone Deacetylase 1

Zhang

Liu

et al. 2014

Molecular and Cellular Biology

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ELL (eleven-nineteen lysine-rich leukemia protein) was first identified as a translocation partner of MLL in acute myeloid leukemia; however, the exact mechanism of its action has remained elusive. In this study, we identified ELL as a direct downstream target gene of E2F1. Coimmunoprecipitation assays showed that ELL interacted with E2F1 in vitro and in vivo, leading to inhibition of E2F1 transcriptional activity. In addition, ELL enhanced E2F1 deacetylation via recruitment of histone deacetylase 1 (HDAC1). Notably, the MLL-ELL fusion protein lost the inhibitory role of ELL in E2F1 transcriptional activity. Furthermore, DNA damage induced ELL in an E2F1-dependent manner and ELL protected cells against E2F1-dependent apoptosis. Our findings not only connect ELL to E2F1 function and uncover a novel role of ELL in response to DNA damage but also provide an insight into the mechanism for MLL-ELL-associated leukemogenesis. The ELL (eleven-nineteen lysine-rich leukemia) protein was first identified as a translocation partner of MLL in acute myeloid leukemia (AML) (1). Subsequent studies showed that ELL can serve as a transcription elongation factor that increases the rate of RNA polymerase II transcriptional elongation by preventing transient pausing (2, 3) or by facilitating RNA polymerase II pause site entry and release (4). Increasing evidence strongly supports the idea that ELL belongs to a super elongation complex that modulates gene expression in development and disease (5-10). In addition, the targeted knockout of ELL in mice causes embryonic lethality, suggesting that ELL has a crucial role in early embryogenesis (11). ELL has been also identified as a partner of steroid receptors p53, hypoxia-inducible factor 1␣ (HIF-1␣), and EAF1/2, modulating their binding partner activity in either a positive or negative manner (12-15). While multiple lines of evidence point to the importance of ELL in normal and cancerous cells, the exact mechanism of its activity remains elusive.The E2F family of transcription factors play important roles in regulating cell cycle progression by transactivating genes required for entry into the S phase (16). As a member of the family, E2F1 also has crucial roles in regulating apoptosis via stimulating the transcription of several genes in the apoptotic pathway, particularly upon DNA damage (17). DNA damage stabilizes and activates E2F1 through phosphorylation by ATM (18) or CHK2 (19), as well as acetylation by PCAF (20). To understand the underlying mechanism of E2F1 activity, multiple investigators have explored the binding partners of E2F1. Studies have shown that the classic tumor suppressor pRb serves as a major regulator of E2F1 (21) by directly recruiting histone deacetylase 1 (HDAC1) (22). pRb is often mutated and inactive in tumors, leading to deregulation of E2F1 activity (23). TopBP1 also interacts with E2F1 and subsequently inhibits E2F1 activity through a Brg1/Brm-dependent, pRb-independent mechanism (24). MCPH1/BRIT1 cooperates with E2F1 to regulate the expression of E2F tar...

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ELL is an HIF‐1α partner that regulates and responds to hypoxia response in PC3 cells

Cited by 12 publications

References 32 publications

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

Regulation of Fertility, Survival, and Cuticle Collagen Function by the Caenorhabditis elegans eaf-1 and ell-1 Genes

ELL Inhibits E2F1 Transcriptional Activity by Enhancing E2F1 Deacetylation via Recruitment of Histone Deacetylase 1

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