Modulation Of Post-translational Modifications Research Articles

The Potential of Hsp90 in Targeting Pathological Pathways in Cardiac Diseases

Heat shock protein 90 (Hsp90) is a molecular chaperone that interacts with up to 10% of the proteome. The extensive involvement in protein folding and regulation of protein stability within cells makes Hsp90 an attractive therapeutic target to correct multiple dysfunctions. Many of the clients of Hsp90 are found in pathways known to be pathogenic in the heart, ranging from transforming growth factor (TGF-) and mitogen activated kinase (MAPK) signaling to tumor necrosis factor (TNF), Gs and Gq g-protein coupled receptor (GPCR) and calcium (Ca2+) signaling. These pathways can therefore be targeted through modulation of Hsp90 activity. The activity of Hsp90 can be targeted through small-molecule inhibition. Small-molecule inhibitors of Hsp90 have been found to be cardiotoxic in some cases however. In this regard, specific targeting of Hsp90 by modulation of post-translational modifications (PTMs) emerges as an attractive strategy. In this review, we aim to address how Hsp90 functions, where Hsp90 interacts within pathological pathways, and current knowledge of small molecules and PTMs known to modulate Hsp90 activity and their potential as therapeutics in cardiac diseases.

Regulation of Sirtuin-Mediated Protein Deacetylation by Cardioprotective Phytochemicals.

Modulation of posttranslational modifications (PTMs), such as protein acetylation, is considered a novel therapeutic strategy to combat the development and progression of cardiovascular diseases. Protein hyperacetylation is associated with the development of numerous cardiovascular diseases, including atherosclerosis, hypertension, cardiac hypertrophy, and heart failure. In addition, decreased expression and activity of the deacetylases Sirt1, Sirt3, and Sirt6 have been linked to the development and progression of cardiac dysfunction. Several phytochemicals exert cardioprotective effects by regulating protein acetylation levels. These effects are mainly exerted via activation of Sirt1 and Sirt3 and inhibition of acetyltransferases. Numerous studies support a cardioprotective role for sirtuin activators (e.g., resveratrol), as well as other emerging modulators of protein acetylation, including curcumin, honokiol, oroxilyn A, quercetin, epigallocatechin-3-gallate, bakuchiol, tyrosol, and berberine. Studies also point to a cardioprotective role for various nonaromatic molecules, such as docosahexaenoic acid, alpha-lipoic acid, sulforaphane, and caffeic acid ethanolamide. Here, we review the vast evidence from the bench to the clinical setting for the potential cardioprotective roles of various phytochemicals in the modulation of sirtuin-mediated deacetylation.

Posttranslational Modifications of Lipid-Activated Nuclear Receptors: Focus on Metabolism.

Posttranslational modifications (PTMs) occur to nearly all proteins, are catalyzed by specific enzymes, and are subjected to tight regulation. They have been shown to be a powerful means by which the function of proteins can be modified, resulting in diverse effects. Technological advances such as the increased sensitivity of mass spectrometry–based techniques and availability of mutant animal models have enhanced our understanding of the complexities of their regulation and the effect they have on protein function. However, the role that PTMs have in a pathological context still remains unknown for the most part. PTMs enable the modulation of nuclear receptor function in a rapid and reversible manner in response to varied stimuli, thereby dramatically altering their activity in some cases. This review focuses on acetylation, phosphorylation, SUMOylation, and O-GlcNAcylation, which are the 4 most studied PTMs affecting lipid-regulated nuclear receptor biology, as well as on the implications of such modifications on metabolic pathways under homeostatic and pathological situations. Moreover, we review recent studies on the modulation of PTMs as therapeutic targets for metabolic diseases.

Modulation of post-translational modifications in β-catenin and LRP6 inhibits Wnt signaling pathway in pancreatic cancer

β-Catenin/Wnt signaling pathway is critically regulated in a normal cell by a number of post-translational modifications. In pancreatic cancer however, aberrant activation of this pathway plays a significant role in tumor progression and metastasis. Though a number of studies have focused on understanding Wnt signaling pathway in pancreatic cancer, there has been no systematic study to evaluate molecules that may be affecting this pathway. In the current study, we used a diterpene triepoxide, triptolide, to inhibit post-translational modifications in Wnt pathway and evaluated how this compound may be affecting the intricate signaling that regulates cell proliferation in pancreatic cancer.Our results showed that triptolide inhibits the activation of WNT1, FZD1, and disheveled (DSH) in pancreatic cancer cell lines MIA PaCa-2 and S2-VP10 by inhibiting the phosphorylation of LRP6 and simultaneously blocked translocation of β-catenin to the nucleus by inhibiting its glycosylation.Additionally, inhibition of post-translational modification of the Wnt-signaling pathway also demonstrated regression of tumor growth in a Syngenic Tumor Implantation Model (STIM). Interestingly, these findings suggest Wnt signaling is a vital molecular pathway in pancreatic cancer and may be amenable to targeted drug therapy.

Characterization of histone post-translational modifications during virus infection using mass spectrometry-based proteomics

Viruses are obligate intracellular parasites that necessarily rely on hijacking cellular resources to produce viral progeny. The success of viral infection requires manipulation of host chromatin in order to activate genes useful for production of viral proteins as well as to suppress antiviral responses. Host chromatin manipulation on a global level is likely reliant on modulation of post-translational modifications (PTMs) on histone proteins. Mass spectrometry (MS) is a powerful tool to quantify and identify novel histone PTMs, beyond the limitations of site-specific antibodies. Here, we employ MS to investigate global changes in histone PTM relative abundance in human cells during infection with adenovirus. Our method reveals several changes in histone PTM patterns during infection. We propose that this method can be used to uncover global changes in histone PTM patterns that are universally modulated by viruses to take over the cell.

Revisiting PPARγ as a target for the treatment of metabolic disorders.

As the prevalence of obesity has increased explosively over the last several decades, associated metabolic disorders, including type 2 diabetes, dyslipidemia, hypertension, and cardiovascular diseases, have been also increased. Thus, new strategies for preventing and treating them are needed. The nuclear peroxisome proliferator-activated receptors (PPARs) are involved fundamentally in regulating energy homeostasis; thus, they have been considered attractive drug targets for addressing metabolic disorders. Among the PPARs, PPARγ is a master regulator of gene expression for metabolism, inflammation, and other pathways in many cell types, especially adipocytes. It is a physiological receptor of the potent anti-diabetic drugs of the thiazolidinediones (TZDs) class, including rosiglitazone (Avandia). However, TZDs have undesirable and severe side effects, such as weight gain, fluid retention, and cardiovascular dysfunction. Recently, many reports have suggested that PPARγ could be modulated by post-translational modifications (PTMs), and modulation of PTM has been considered as novel approaches for treating metabolic disorders with fewer side effects than the TZDs. In this review, we discuss how PTM of PPARγ may be regulated and issues to be considered in making novel anti-diabetic drugs that can modulate the PTM of PPARγ. [BMB Reports 2014; 47(11): 599-608]

Modifications of CD40 regulate defective CD40 signals in B cells from a patient with non-X-linked hyper IgM syndrome (HIGM) (35.13)

Abstract Our previous studies have demonstrated a CD40 signaling defect in B cells from a patient with non-X-linked HIGM (pt1). To elucidate the cause for impaired CD40 signals, we utilized a mini-EBV transformed cell line with inducible latent membrane protein 1 (LMP1) expression (LCLtet). The LMP1 signaling pathway appears to be intact, however CD40 activation was unable to promote cell division and transcriptional synthesis of cMyc in pt1-LCLtet cells. We examined mediators of the CD40 signaling pathway and found impaired localization of CD40 to microdomains, thereby impeding TNF receptor-associated factor recruitment and degradation after 2h of CD40 activation. However, prolonged CD40 ligation was sufficient to induce proper CD40 distribution, suggesting that the pt1 B cells possess a higher CD40 activation threshold that requires a greater magnitude of extensive and sustained CD40 signals to achieve signal transmission. Furthermore, pt1 B cells have a unique CD40 expression profile, indicative of an isoform with post-translational modifications. Specifically, CD40 on pt1 B cells is constitutively hyperphosphorylated and not differentially regulated by LMP1 or CD40 signals. These data collectively suggest that modulation of post-translational modifications, which mediate CD40 function and activity, may provide further insight into the cause of defective CD40 signals in this unique form of HIGM. (AI37081)