Metabolic Control of Proteasome Function

Zhang, Fengxue; Paterson, Andrew J.; Huang, Ping; Wang, Kai; Kudlow, Jeffrey E.

doi:10.1152/physiol.00026.2007

Cited by 31 publications

(27 citation statements)

References 76 publications

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“…Significantly, PKA has been reported as a major regulator of proteasome activity and co-purifies with the proteasome (57, 58). Furthermore, PKA activation has been shown to enhance the chymotrypsin activity of the proteasome (59) and increase the transport function of the Rpt6 subunit of the 19 S outer ring (60). Although the strategic use of proteasomal inhibitors in combination with HDACis as potential anticancer drugs is in a nascent stage, we made the novel observation that belinostat at early time points significantly increased the chymotrypsin proteasomal activity.…”

Section: Discussionmentioning

confidence: 93%

Histone Deacetylase Inhibitor Belinostat Represses Survivin Expression through Reactivation of Transforming Growth Factor β (TGFβ) Receptor II Leading to Cancer Cell Death

Chowdhury

Howell

Teggart

et al. 2011

Journal of Biological Chemistry

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Survivin is a cancer-associated gene that functions to promote cell survival, cell division, and angiogenesis and is a marker of poor prognosis. Histone deacetylase inhibitors induce apoptosis and re-expression of epigenetically silenced tumor suppressor genes in cancer cells. In association with increased expression of the tumor suppressor gene transforming growth factor ␤ receptor II (TGF␤RII) induced by the histone deacetylase inhibitor belinostat, we observed repressed survivin expression. We investigated the molecular mechanisms involved in survivin down-regulation by belinostat downstream of reactivation of TGF␤ signaling. We identified two mechanisms. At early time points, survivin protein half-life was decreased with its proteasomal degradation. We observed that belinostat activated protein kinase A at early time points in a TGF␤ signaling-dependent mechanism. After longer times (48 h), survivin mRNA was also decreased by belinostat. We made the novel observation that belinostat mediated cell death through the TGF␤/protein kinase A signaling pathway. Induction of TGF␤RII with concomitant survivin repression may represent a significant mechanism in the anticancer effects of this drug. Therefore, patient populations exhibiting high survivin expression with epigenetically silenced TGF␤RII might potentially benefit from the use of this histone deacetylase inhibitor.The mutational events involved in the initiation and progression of colorectal cancer have been well documented (1). However, it is now recognized that in addition to these alterations in DNA sequence epigenetic modifications of the genome play a major role in contributing to the malignant phenotype (1, 2). The critical balance between histone acetylation by histone acetyltransferases and deacetylation by histone deacetylases (HDACs) 3 represents a key epigenetic layer involved in gene regulation (3). The class I HDACs are overexpressed in many tumor types compared with normal tissues (4), and this overexpression is generally associated with poor prognosis (5, 6). These findings have resulted in the development of drugs that target HDACs. The second generation HDAC inhibitors (HDACis) target class I and II HDACs. These drugs induce differentiation, cell growth arrest, and apoptosis in cell lines in vitro and in vivo indicating that the increased activity of these enzymes in cancer contributes to tumor progression (7-9). However, the key mechanisms and pathways through which HDAC inhibition leads to tumor cell apoptosis have not been well defined.Transforming growth factor ␤ (TGF␤) signaling has been shown to contribute to a variety of cellular functions including growth inhibition and induction of differentiation and apoptosis as well as cell motility and adhesion (10). It has been demonstrated that transcriptional loss of TGF␤ receptor expression leading to attenuation of TGF␤ signaling is a frequent occurrence in a wide range of cancers in vitro and in vivo and is associated with poor patient prognosis (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(...

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Section: Discussionmentioning

confidence: 93%

Histone Deacetylase Inhibitor Belinostat Represses Survivin Expression through Reactivation of Transforming Growth Factor β (TGFβ) Receptor II Leading to Cancer Cell Death

Chowdhury

Howell

Teggart

et al. 2011

Journal of Biological Chemistry

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“…In the starved muscle, reduced O-GlcNAc signaling promotes the ability of the proteasome to degrade polyubiquitinated proteins (72). Meanwhile, O-GlcNAc signaling in the liver promotes gluconeogenesis by deubiquitinating and stabilizing PGC-1␣ and CRTC2 (13,37,73).…”

Section: O-glcnacylation Regulates Protein Ubiquitination Via Unknownmentioning

confidence: 99%

Regulation of Protein Degradation by O-GlcNAcylation: Crosstalk with Ubiquitination

Ruan

Nie

Yang

2013

Molecular & Cellular Proteomics

148

119

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The post-translational modification of intracellular proteins by O-linked N-acetylglucosamine (O-GlcNAc) regulates essential cellular processes such as signal transduction, transcription, translation, and protein degradation. Misfolded, damaged, and unwanted proteins are tagged with a chain of ubiquitin moieties for degradation by the proteasome, which is critical for cellular homeostasis. In this review, we summarize the current knowledge of the interplay between O-GlcNAcylation and ubiquitination in the control of protein degradation. Understanding the mechanisms of action of O-GlcNAcylation in the ubiquitin-proteosome system shall facilitate the development of therapeutics for human diseases such as cancer, metabolic syndrome, and neurodegenerative diseases. Molecular & Cellular

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“…Interferon-␥ triggers a decrease in phosphorylation of both 20S and 19S subunits, leading to the disassembly of 26S proteasomes in response to stress (59). PKA induced the phosphorylation of Rpt6 and O-GlcNAc modification of Rpt2 coordinate glucose metabolism (77). In addition, PKA and protein phosphatase 2A play antagonistic roles in regulating proteasomal function (80).…”

Section: Future Directionsmentioning

confidence: 99%

Post-translational modification of cardiac proteasomes: functional delineation enabled by proteomics

Scruggs

Zong

Wang

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Proteasomes are ubiquitously expressed multicatalytic complexes that serve as key regulators of protein homeostasis. There are several lines of evidence indicating that proteasomes exist in heterogeneous subpopulations in cardiac muscle, differentiated, in part, by post-translational modifications (PTMs). PTMs regulate numerous facets of proteasome function, including catalytic activities, complex assembly, interactions with associating partners, subcellular localization, substrate preference, and complex turnover. Classical technologies used to identify PTMs on proteasomes have lacked the ability to determine site specificity, quantify stoichiometry, and perform large-scale, multi-PTM analysis. Recent advancements in proteomic technologies have largely overcome these limitations. We present here a discussion on the importance of PTMs in modulating proteasome function in cardiac physiology and pathophysiology, followed by the presentation of a state-of-the-art proteomic workflow for identifying and quantifying PTMs of cardiac proteasomes.

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Metabolic Control of Proteasome Function

Cited by 31 publications

References 76 publications

Histone Deacetylase Inhibitor Belinostat Represses Survivin Expression through Reactivation of Transforming Growth Factor β (TGFβ) Receptor II Leading to Cancer Cell Death

Histone Deacetylase Inhibitor Belinostat Represses Survivin Expression through Reactivation of Transforming Growth Factor β (TGFβ) Receptor II Leading to Cancer Cell Death

Regulation of Protein Degradation by O-GlcNAcylation: Crosstalk with Ubiquitination

Post-translational modification of cardiac proteasomes: functional delineation enabled by proteomics

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