Nuclear hormone receptor degradation and gene transcription: An update

Ismail, Azman; Nawaz, Zafar

doi:10.1080/15216540500147163

Cited by 46 publications

(23 citation statements)

References 66 publications

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“…Consistent with these results, ubiquitin-dependent mechanisms induce heterochromatin relaxation, facilitate assembly of transcription complexes on promoters, and enhance transcriptional activation capacity of transcription factors but also target transcriptional coactivators and corepressors for degradation (7,22,33).…”

Section: Discussionsupporting

confidence: 60%

MKL1 mediates TGF-β1-induced α-smooth muscle actin expression in human renal epithelial cells

Elberg¹,

Chen²,

Elberg³

et al. 2008

American Journal of Physiology-Renal Physiology

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Elberg G, Chen L, Elberg D, Chan MD, Logan CJ, Turman MA. MKL1 mediates TGF-␤1-induced ␣-smooth muscle actin expression in human renal epithelial cells. Am J Physiol Renal Physiol 294: F1116-F1128, 2008. First published March 12, 2008 doi:10.1152/ajprenal.00142.2007.-Transforming growth factor-␤1 (TGF-␤1) is known to induce epithelial-mesenchymal transition in the kidney, a process involved in tubulointerstitial fibrosis. We hypothesized that a coactivator of the serum response factor (SRF), megakaryoblastic leukemia factor-1 (MKL1), stimulates ␣-smooth muscle actin (␣-SMA) transcription in primary cultures of renal tubular epithelial cells (RTC), which convert into myofibroblasts on treatment with TGF-␤1. Herein, we study the effect of MKL1 expression on ␣-SMA in these cells. We demonstrate that TGF-␤1 stimulation of ␣-SMA transcription is mediated through CC(A/T) 6-rich GG elements known to bind to SRF. These elements also mediate the MKL1 effect that dramatically activates ␣-SMA transcription in serum-free media. MKL1 fused to green fluorescent protein localizes to the nucleus and induces ␣-SMA expression regardless of treatment with TGF-␤1. Using proteasome inhibitors, we also demonstrate that the proteolytic ubiquitin pathway regulates MKL1 expression. These data indicate that MKL1 overexpression is sufficient to induce ␣-SMA expression. Inhibition of endogenous expression of MKL1 by small interfering RNA abolishes TGF-␤1 stimulation of ␣-SMA expression. Therefore, MKL1 is also absolutely required for TGF-␤1 stimulation of ␣-SMA expression. Western blot and immunofluorescence analysis show that overexpressed and endogenous MKL1 are located in the nucleus in non-stimulated RTC. Chromatin immunoprecipitation assay demonstrates that TGF-␤1 induces binding of endogenous SRF and MKL1 to the ␣-SMA promoter in chromatin. Since MKL1 constitutes a potent factor regulating ␣-SMA expression, modulation of endogenous MKL1 expression or activity may have a profound effect on myofibroblast formation and function in the kidney.epithelial-mesenchymal transition; myocardin; ubiquitin; transcription; myofibroblast RENAL FIBROSIS IS A COMMON feature of various kidney diseases leading to end-stage renal failure (15,44). This process is characterized by the accumulation of myofibroblasts defined by the expression of ␣-smooth muscle actin (␣-SMA). These cells are major contributors to the increased extracellular matrix deposition seen in kidney fibrosis (16,69). A number of studies demonstrate that renal tubular cells (RTC) can convert to myofibroblasts on epithelial-mesenchymal transition (EMT) stimulated by transforming growth factor-␤ (TGF-␤) (9,11,24,45,69).The regulation of ␣-SMA transcription has been extensively studied in smooth muscle cells and in cells from the myocardium and skeletal muscle, which express ␣-SMA in adults and embryos, respectively (66). Studies on the ␣-SMA promoter from chickens, rats, mice, and humans highlight the importance of cell context and species differences for ␣-SMA transcriptional regulat...

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Section: Discussionsupporting

confidence: 60%

MKL1 mediates TGF-β1-induced α-smooth muscle actin expression in human renal epithelial cells

Elberg¹,

Chen²,

Elberg³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…Finally, the ubiquitin-tagged target proteins undergo degradation via the 26S proteasome pathway. Since, E6-AP acts both as a coactivator and an E3 ubiquitin-protein ligase, it is postulated that E6-AP serves to link two important and opposing activities in a cell, the transcription and the protein degradation [6, 7]. …”

Section: Introductionmentioning

confidence: 99%

E3 ubiquitin protein ligase, E6-associated protein (E6-AP) regulates PI3K-Akt signaling and prostate cell growth

Srinivasan

Nawaz

2011

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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This study elucidates the role of E6-associated protein, E6-AP (a dual function steroid hormone receptor coactivator and ubiquitin-protein ligase) in the regulation of PI3K-Akt signaling pathway, prostate gland growth and proliferation. Here, we report the generation of transgenic mice and prostate cancer cell line, LNCaP cells that overexpress E6-AP protein. Using these models we show that the levels of total Akt and phosphorylated Akt (active Akt) are increased in E6-AP overexpressing prostate gland and LNCaP cells suggesting that E6-AP regulates the PI3K-Akt signaling pathway. The prostate glands in our transgenic mice are ~20% larger and produce preneoplastic lesions at the age of 18 months. Our data also suggest that E6-AP modulates PI3K-Akt signaling pathway by both androgen-independent and -dependent mechanisms. In the androgen-independent mechanism, E6-AP modulates PI3K-Akt signaling by regulating the protein levels of RhoA, a small GTPase, which is a negative regulator of the Akt signaling pathway. Further, we show that E6-AP, a known coactivator of AR, amplifies the androgen-dependent activation of PI3K-Akt signaling pathway. In addition, we show that stable overexpression of E6-AP in prostate cancer cells results in increased cell size and proliferation. Overall our data suggests that E6-AP regulates both the positive and negative modulators of the PI3K-Akt pathway in prostate cells which results in increased prostate cell growth, proliferation and decreased apoptosis.

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“…Therefore, identification of corepressors for ligand bound NRs provides insights into hormone regulated transcriptional repression mechanisms. More evidence documents that transcriptional activation is a dynamic process, involving many cofactors cycling on the target promoter in a temporal and sequential manner [Hager et al, 2004; Ismail and Nawaz, 2005]. However, not many studies have been done in liganded nuclear receptor‐mediated transcriptional repression.…”

Section: Discussionmentioning

confidence: 99%

RIF‐1, a novel nuclear receptor corepressor that associates with the nuclear matrix

Li¹,

Haque²,

Chen³

et al. 2007

J of Cellular Biochemistry

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The retinoic acid receptors (RARs) are ligand-dependent transcription factors that play critical roles in cell differentiation, embryonic development, and tumor suppression. RAR transcriptional activities are mediated by a growing family of nuclear receptor (NR) coregulators. Here we report the cloning and characterization of a novel protein RIF1 (receptor interacting factor) that interacts with RARalpha in vivo and in vitro. RIF1 encodes a novel 739 amino acid protein that is ubiquitously expressed in a variety of tissues and cell lines. GST-pull down assays show that RIF1 also interacts with a number of other NRs. The interaction domain of RIF1 for RARalpha is located at the C-terminal region of RIF1, between amino acids 512 and 674. RIF1 is localized exclusively in the cell nucleus and specifically to the nuclear matrix. Mutation of the nuclear localization signal abolishes this nuclear localization and causes RIF1 to appear in the cytoplasm. Co-transfection of RIF1 with RAR causes RAR to localize to the nuclear matrix. RIF1 contains a strong transcriptional repression domain that robustly inhibits ligand-dependent transcriptional activation by RARalpha. This domain is located to the distal C-terminal 100 amino acids, distinct from the RARalpha-interaction and nuclear matrix-targeting domains. The transcriptional repression activity of RIF1 is mediated at least in part through direct recruitment of histone deacetylases. This study identifies RIF1 as a novel nuclear matrix transcription repressor, and suggests a potential role of RIF1 that regulates NR transcriptional activity.

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Nuclear hormone receptor degradation and gene transcription: An update

Cited by 46 publications

References 66 publications

MKL1 mediates TGF-β1-induced α-smooth muscle actin expression in human renal epithelial cells

MKL1 mediates TGF-β1-induced α-smooth muscle actin expression in human renal epithelial cells

E3 ubiquitin protein ligase, E6-associated protein (E6-AP) regulates PI3K-Akt signaling and prostate cell growth

RIF‐1, a novel nuclear receptor corepressor that associates with the nuclear matrix

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