MDM2 interacts with and downregulates a sarcomeric protein, TCAP

Tian, Li; Li, Hui Yan; Jin, Bao Feng; Pan, Xin; Man, Jiang Hong; Zhang, Pei Jing; Li, Weihua; Liu, Bing; Liu, Hui; Zhao, Jie; Gong, Wenbin; Zhou, Tao; Zhang, Xue Min

doi:10.1016/j.bbrc.2006.04.108

Cited by 41 publications

(34 citation statements)

References 31 publications

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“…Overexpression of MDM2 has been shown to enhance cardiocyte survival under hypoxic conditions, while decreased expression impaired functional recovery from ischemia-reperfusion in isolated, perfused hearts [25]. Furthermore, it has been found to interact with TCAP, a sarcomeric protein important in the development of muscle hypertrophy [26]. These findings show that acute pressure overload mobilizes several functional classes of mRNA for translation, all of which have established roles during the process of cardiac hypertrophy, remodeling and survival.…”

Section: Discussionmentioning

confidence: 93%

Selective translation of mRNAs in the left ventricular myocardium of the mouse in response to acute pressure overload

Spruill¹,

Baicu²,

Zile³

et al. 2008

Journal of Molecular and Cellular Cardiology

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During pressure overload hypertrophy, selective changes in cardiac gene expression occur that regulate growth and modify the structural and functional properties of the myocardium. To determine the role of translational mechanisms, a murine model of transverse aortic constriction was used to screen a set of specified mRNAs for changes in translational activity by measuring incorporation into polysomes in response to acute pressure overload. Candidate mRNAs were selected on the basis of two main criteria: 1) the 5′-untranslated region of the mRNA contains an excessive amount of secondary structure (ΔG < −50 kCal/mol), which is postulated to regulate efficiency of translation, and 2) the protein product has been implicated in the regulation of cardiac hypertrophy. After 24 hours of transverse aortic constriction, homogenates derived from the left ventricle were layered onto 15%-50% linear sucrose gradients and resolved into monosome fractions (messenger ribonucleoprotein particles) and polysome fractions by density gradient ultracentrifugation. The levels of mRNA in each fraction were quantified by real-time RT-PCR. The screen revealed that pressure overload increased translational activity of 6 candidate mRNAs as determined by a significant increase in the percentage of total mRNA incorporated into the polysome fractions. The mRNAs code for several functional classes of proteins linked to cardiac hypertrophy: the transcription factors c-myc, c-jun and MEF2D, growth factors VEGF and FGF-2, and the E3 ubiquitin ligase MDM2. These studies demonstrate that acute pressure overload alters cardiac gene expression by mechanisms that selectively regulate translational activity of specific mRNAs.

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Section: Discussionmentioning

confidence: 93%

Selective translation of mRNAs in the left ventricular myocardium of the mouse in response to acute pressure overload

Spruill¹,

Baicu²,

Zile³

et al. 2008

Journal of Molecular and Cellular Cardiology

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“…31,34,35 The well-documented strong binding of telethonin to the Ig1/Ig2 domains 33 is not crucial for anchoring titin firmly to the Z-disk. 36 Telethonin interacts, among others, with the E3 ubiquitin ligase mouse-double-minute-2-homolog, 37 which links Z-disk titin to the ubiquitin-proteasomal degradation pathway (Figure 3). Interactions with nebulin/nebulette 38 and filamin-C 39 connect the first unique sequence at titin's NH 2 terminus to other components of the intra-and extrasarcomeric cytoskeleton ( Figure 2B), providing additional structural stability.…”

Section: Titin Functions Acquired Through Ligand Bindingmentioning

confidence: 99%

Gigantic Business

Linke

Hamdani

2014

Circulation Research

292

232

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With every heartbeat, our cardiomyocytes are exposed to variable degrees of stress and strain of both internal and external origin. The unique mechanical properties of these myocytes are determined by the sarcomeric cytoskeleton. The actin (thin) and myosin (thick) filaments of the sarcomere are mainly relevant for active force generation, whereas the titin filaments determine sarcomeric viscoelasticity. The giant protein titin, which is the focus of this review, has various roles beyond viscoelastic force generation 1-3 : (1) it keeps the thick filaments centered in the sarcomere, allowing optimum active force development; (2) it is important for the assembly of the sarcomeres; (3) it participates in mechano-chemical signaling events via some of its binding partners; and (4) it may be crucial for the length-dependent activation of the contractile apparatus, which underlies the Frank-Starling law. During the past decade, we have learned that titin elasticity is highly variable in the developing and the adult healthy heart and that it can be pathologically altered in heart disease. These alterations greatly affect the extensibility and the diastolic passive stiffness of myocardium and presumably also the mechanosensitivity. Moreover, TTN, which encodes the titin protein, has been recognized as a major human disease gene. In this context, the properties and functions of cardiac titin have become of interest in the continuing search for the molecular origins of human heart disease and the identification of novel potential targets for therapeutic intervention. In our review, we begin with a short clinical perspective establishing the link between diastolic stiffness and titin and briefly compare the importance of titin versus collagen for myocardial passive stiffness. We then cover some details of titin protein structure and elasticity, before summarizing how titin-binding partners affect titin properties and broaden the range of titin functions, with a special focus on the standing of titin in pathways of protein quality control. We continue with a current overview of titin mutations in human skeletal muscle and heart disease. The remainder of the review deals with the contribution of titin to diastolic stiffness and how it is modulated in normal and failing hearts by mechanisms such as titin-isoform switching, titin phosphorylation (including heart failure [HF]-related alterations of it), and oxidative modifications. Clinical Context: Diastolic Function and Diastolic AbnormalitiesDiastolic function has moved into the focus of HF research, because an increasing number of patients with HF (≥50%) present with diastolic rather than systolic dysfunction. 4 Common abnormalities of diastolic function include impaired left ventricular (LV) relaxation, decreased LV distensibility, increased LV end-diastolic stiffness, and pericardial and right ventricular constraint. These abnormalities have been suggested to be contributing factors in diastolic HF or HF with a preserved ejection fraction (HFpEF).5 HFpEF is accompanied by ...

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“…23 On the basis of its activity toward p53, MDM2 is logically necessary for cardiac myocyte responses to hypoxia and ischemic injury. 24 It is less self-evident that MDM2 would play a role in the cardiac hypertrophic response, but MDM2 overexpression promotes survival and prevents hypertrophy induced by adrenergic stimulation; indeed, the antihypertrophic effect of MDM2 may be independent of its ubiquitin ligase activity, 25 although a deeper understanding of this phenomenon is required.…”

Section: Other Ubiquitin Ligasesmentioning

confidence: 99%

The Bitter End

et al. 2007

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Abstract-Many elements contribute to congestive heart failure: changes in perfusion, hemodynamic stresses, alterations in calcium metabolism, and dysregulation of cell signaling pathways. Intervention in these processes forms the basis for current heart failure therapies. Nevertheless, heart failure is primarily a disease of wear and tear; despite everything we know about cardiac physiology and the clinical manifestations of heart failure, only in rare instances does therapy for heart failure normalize cardiac function. Proteins are especially prone to the forces of wear and tear in the heart because they are the primary mechanisms for stress sensing and force generation. Recent evidence supports a role for protein damage and impaired clearance of damaged proteins in the pathophysiology of human heart failure syndromes. The process of monitoring and protecting cardiac cells from accumulation of damaged proteins is known as protein quality control, and the molecular chaperone and ubiquitin-proteasome systems are the primary effectors of this process.Insights from protein quality-control strategies may lead to new concepts about prevention and treatment of human heart failure. This review provides a general overview of these pathways and their known and postulated roles in human heart failure syndromes, with a focus on providing a clinically oriented understanding of these fundamental mechanisms.

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MDM2 interacts with and downregulates a sarcomeric protein, TCAP

Cited by 41 publications

References 31 publications

Selective translation of mRNAs in the left ventricular myocardium of the mouse in response to acute pressure overload

Selective translation of mRNAs in the left ventricular myocardium of the mouse in response to acute pressure overload

Gigantic Business

The Bitter End

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