Back to your heart: Ubiquitin proteasome system-regulated signal transduction

Portbury, Andrea L.; Ronnebaum, Sarah M.; Zungu, Makhosazane; Patterson, W. Cam; Willis, Monte S.

doi:10.1016/j.yjmcc.2011.10.023

Cited by 85 publications

(62 citation statements)

References 157 publications

(195 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The post-translational modification of apoptotic proteins by ubiquitination regulates key components of programmed cell death signaling cascades (48,55,63,68). Similar to the findings of Tsukamoto et al (63) in LVH/LVF, decreases in proteasome activity were associated with decreases in antiapoptotic proteins and increases in pro-apoptotic proteins and TUNEL-positive nuclei.…”

Section: Discussionsupporting

confidence: 78%

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

Rajagopalan

Zhao

Reddy

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Alterations in the ubiquitin-proteasome system (UPS) have been described in left ventricular hypertrophy and failure, although results have been inconsistent. The role of the UPS in right ventricular (RV) hypertrophy (RVH) and RV failure (RVF) is unknown. Given the greater percent increase in RV mass associated with RV afterload stress, as present in many congenital heart lesions, we hypothesized that alterations in the UPS could play an important role in RVH/RVF. UPS expression and activity were measured in the RV from mice with RVH/RVF secondary to pulmonary artery constriction (PAC). Epoxomicin and MG132 were used to inhibit the proteasome, and overexpression of the 11S PA28␣ subunit was used to activate the proteasome. PAC mice developed RVH (109.3% increase in RV weight to body weight), RV dilation with septal shift, RV dysfunction, and clinical RVF. Proteasomal function (26S ␤5 chymotrypsin-like activity) was decreased 26% (P Ͻ 0.05). Protein expression of 19S subunit Rpt5 (P Ͻ 0.05), UCHL1 deubiquitinase (P Ͻ 0.0001), and Smurf1 E3 ubiquitin ligase (P Ͻ 0.01) were increased, as were polyubiquitinated proteins (P Ͻ 0.05) and free-ubiquitins (P ϭ 0.05). Pro-apoptotic Bax was increased (P Ͻ 0.0001), whereas anti-apoptotic Bcl-2 decreased (P Ͻ 0.05), resulting in a sixfold increase in the Bax/Bcl-2 ratio. Proteasomal inhibition did not accelerate RVF. However, proteasome enhancement by cardiacspecific proteasome overexpression partially improved survival. Proteasome activity is decreased in RVH/RVF, associated with upregulation of key UPS regulators and pro-apoptotic signaling. Enhancement of proteasome function partially attenuates RVF, suggesting that UPS dysfunction contributes to RVF. ubiquitin; proteasome; right ventricle; cardiac hypertrophy; heart failure PATHOLOGIC HYPERTROPHY IS an important adaptation to stressors varying from ischemia to hypertension as well as many forms of congenital heart disease. Chronic hypertrophy-inducing stress can lead to fibrosis, decreased contractile function, and ultimately heart failure. Pressure overload hypertrophy is associated with a marked increase in protein synthesis at a rate exceeding degradation (57), the most dramatic the heart experiences since early development. Under normal circumstances, the proteins of the heart turn over at a rate that would replace all in 30 days (15,33,50). More than 70% of protein turnover is regulated by the ubiquitin-proteasome system (UPS) (18,56,74), involving signaling the target by covalent attachment of ubiquitin and degradation of tagged proteins by the 26S proteasome complex with release of ubiquitins by deubiquitinating enzymes. Three peptidase activities, chymotrypsin-like, trypsin-like, and caspase-like activities, have been assigned to the ␤ 5 , ␤ 2 , and ␤ 1 subunits, respectively, of the 20S core proteasomal complex, capped by 19S regulatory and/or 11S activator complexes. The UPS also interacts with lysosomal (autophagy dependent or independent) and other protease-specific pathways within the cardiomyocyte (17, 71)....

show abstract

Section: Discussionsupporting

confidence: 78%

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

Rajagopalan

Zhao

Reddy

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…34). In the JNK signaling pathway alone, at least six proteins with ubiquitin ligase activity have been described, including MEKK1, Fbw7, DCX, itch, MuRF1, and atrogin-1/MAFbx (17,23,25,31,50,58,59).…”

Section: Discussionmentioning

confidence: 99%

“…transduction at the protein level, given the role of ubiquitin ligases in regulating signal transduction (34).…”

Section: Murf1 Inhibits Total Akt Gsk3␤ and Mtor Protein Levels In mentioning

confidence: 99%

“…These data confirm that MuRF1-dependent regulation of IGF-I signaling is applicable in whole animal models and provide additional evidence for the importance of the ubiquitin proteasome system in the heart. The role of ubiquitin ligases in the regulation of IGF-I signaling in the myocardium in vivo is the latest in the growing literature implicating the ubiquitin proteasome system in maintenance of cardiac function (34,36). Mice lacking the ubiquitin ligase and protein chaperone carboxyl terminus of heat shock protein 70-interacting protein (CHIP) exhibit an exaggerated cardiac hypertrophy in as little as 1 wk and as much as 5 wk of running, which parallels increases in increased phosphorylated Akt after IGF-I stimulation in vitro (54).…”

Section: Murf1tgϩmentioning

confidence: 99%

See 1 more Smart Citation

Muscle RING finger-1 attenuates IGF-I-dependent cardiomyocyte hypertrophy by inhibiting JNK signaling

Wadosky

Rodriguez

Hite

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…123 Itch has also been involved in JNK signaling, specifically targeting c-Jun for its degradation in a ubiquitin-mediated manner. 124 Indeed, several lines of experimental evidence recently reviewed by Portbury et al 125 support the concept that both ubiquitination and SUMOylation regulates JNK signal transduction, and that several proteins with ubiquitin ligase activity are involved in cardiovascular JNK signaling.…”

Section: E3-ligases Within the Notch Pathwaymentioning

confidence: 93%

Role of the Ubiquitin Proteasome System in the Heart

Pagan

Seto

Pagano

et al. 2013

Circulation Research

119

View full text Add to dashboard Cite

Abstract:Proper protein turnover is required for cardiac homeostasis and, accordingly, impaired proteasomal function appears to contribute to heart disease. Specific proteasomal degradation mechanisms underlying cardiovascular biology and disease have been identified, and such cellular pathways have been proposed to be targets of clinical relevance. This review summarizes the latest literature regarding the specific E3 ligases involved in heart biology, and the general ways that the proteasome regulates protein quality control in heart disease. The potential for therapeutic intervention in Ubiquitin Proteasome System function in heart disease is discussed. (Circ Res. 2013;112:1046-1058.)

show abstract

Back to your heart: Ubiquitin proteasome system-regulated signal transduction

Cited by 85 publications

References 157 publications

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

Muscle RING finger-1 attenuates IGF-I-dependent cardiomyocyte hypertrophy by inhibiting JNK signaling

Role of the Ubiquitin Proteasome System in the Heart

Contact Info

Product

Resources

About