Ubiquitin and control of transcription

Dhananjayan, Sarath C.; Ismail, Azman; Nawaz, Zafar

doi:10.1042/eb0410069

Cited by 50 publications

(32 citation statements)

References 55 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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“…Increased Ro52 led to enhanced expression of a target gene IL-12p40 rather than promoting IRF-8 degradation. Our results add IRF-8 to a growing list of transcription factors that gain enhanced transcriptional activity upon ubiquitination (2,4,23). Although the mechanism by which ubiquitination enhances transcription remains elusive, ubiquitination may control dynamic assembly/ disassembly of transcription factors at the promoters.…”

Section: Ro52 Enhancement Of Il-12p40 Expressionmentioning

confidence: 92%

Cutting Edge: Autoantigen Ro52 Is an Interferon Inducible E3 Ligase That Ubiquitinates IRF-8 and Enhances Cytokine Expression in Macrophages

Kong

Anderson

Lee

et al. 2007

The Journal of Immunology

180

175

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IFN regulatory factor (IRF)-8 is a transcription factor important for the development and function of macrophages. It plays a critical role in the induction of cytokine genes, including IL-12p40. Immunopurification and mass spectrometry analysis found that IRF-8 interacted with Ro52 in murine macrophages upon IFN-γ and TLR stimulation. Ro52 is an IFN-inducible protein of the tripartite motif (TRIM) family and is an autoantigen present in patients with Sjögren’s syndrome and systemic lupus erythematosus. Ro52 has a RING motif and is capable of ubiquitinating itself. We show that IRF-8 is ubiquitinated by Ro52 both in vivo and in vitro. Ectopic expression of Ro52 enhanced IL-12p40 expression in IFN-γ/TLR-stimulated macrophages in an IRF-8-dependent manner. Together, Ro52 is an E3 ligase for IRF-8 that acts in a non-degradation pathway of ubiquitination, and contributes to the elicitation of innate immunity in macrophages.

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“…However, E6AP has also been implicated in the regulation of gene transcription. 29 We therefore determined at what level(s) E6AP affects PML expression. For this purpose, T blasts from wt or E6AP KO mice were harvested and protein levels were determined by western blot analysis, and mRNA was quantified by quantitative real-time PCR (RT-PCR).…”

Section: E6ap Decreases Pml Protein Levelsmentioning

confidence: 99%

E6AP promotes the degradation of the PML tumor suppressor

et al. 2009

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The promyelocytic leukemia (PML) tumor suppressor is essential for the formation of PML nuclear bodies (NBs). PML and PMLNBs have been implicated in the regulation of growth inhibition, senescence and apoptosis. PML is activated in response to stress signals and is downregulated in certain human cancers. However, the factors mediating PML stability are incompletely understood. Here we demonstrate that a catalytically active form of the mammalian E3 ligase E6AP (HPV E6-associated protein) acts to reduce the half-life of the PML protein by promoting its degradation in the proteasome. E6AP mediates the ubiquitination of PML in an in vitro ubiquitination assay. E6AP and PML interact at physiological levels and colocalize in PML-NBs. Importantly, PML protein expression is elevated in multiple organs and cell types from E6AP null mice and in lymphoid cells is associated with increased number and intensity of PML-NBs. This PML elevation is enhanced in response to DNA damage. Our results identify E6AP as an important regulator of PML and PML-NBs. The promyelocytic leukemia (PML) tumor suppressor is implicated in the regulation of cell-cycle progression, premature senescence (triggered by oncogenic Ras) and apoptosis (reviewed by Bernardi and Pandolfi 1 ). Deregulation of PML can be oncogenic. PML-RARa contributes to acute promyelocytic leukemia (APL) 2,3 and downregulation of PML was observed in multiple human cancers. 4 PML knockout (KO) mice are resistant to lethal doses of ionizing irradiation (IR), and exhibit genomic instability and enhanced susceptibility to tumorigenesis upon exposure to carcinogens 1,5 or in the context of additional oncogenic events (e.g., a loss of Pten 6 ). The myriad of PML functions have been linked to its function in PML nuclear body (PML-NB) formation. 7 These are dynamic structures whose configuration and composition are modified in response to specific stress signals. 8 However, their mechanisms of action are only partially understood and are believed to be mediated by key proteins that are recruited to these structures, including pRb, SUMO, Daxx and p53. 9 The regulation of certain proteins, such as p53, is associated with the PML-NBs. 9 Stress stimuli that have been identified as activators of PML and PML-NBs include interferon (a and g), DNA damage, oncogenic stress and viral infection (reviewed in references 1,8,10 ). In contrast, exposure of cells to arsenic trioxide (As 2 O 3 ) or retinoic acid promotes PML degradation. 11 In contrast, the overexpression of specific cellular ubiquitin ligases, such as the Siah protein, 12 or certain viral ubiquitin ligases, such as the ICP0 regulatory protein of herpesvirus-1, 10 promotes the proteasomal degradation of PML and PML-RARa. However, the nature of the underlying mechanism of this degradation and whether it occurs under physiological conditions is not known. Recently, a function for CK2-mediated phosphorylation of PML (on serine 517) in the control of its protein stability was demonstrated. 13 In addition to phosphorylation, the covalen...

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Ubiquitin and control of transcription

Cited by 50 publications

References 55 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

Cutting Edge: Autoantigen Ro52 Is an Interferon Inducible E3 Ligase That Ubiquitinates IRF-8 and Enhances Cytokine Expression in Macrophages

E6AP promotes the degradation of the PML tumor suppressor

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