Oxidative stress regulated expression of Ubiquitin Carboxyl-terminal Hydrolase-L1: Role in cell survival

Shen, Hui; Sikorska, Marianna; Leblanc, Julie; Walker, P. Roy; Liu, Q. Y.

doi:10.1007/s10495-006-6303-8

Cited by 62 publications

(52 citation statements)

References 55 publications

(63 reference statements)

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“…Thus, one possible mechanism by which UCHL1 functions as tumor suppressor gene is through ubiquitinating oncoproteins and deubiquitinating tumor suppressor genes. Previous studies have shown that UCHL1 promotes the degradation of cell cycle inhibitor p27 kip1 (36,37) and stabilizes NF-κB (38) and p53 (12,19), but the specific substrates of UCHL1 in cancers are largely unclear.…”

Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor UCHL1 Forms a Complex with p53/MDM2/ARF to Promote p53 Signaling and Is Frequently Silenced in Nasopharyngeal Carcinoma

Tao

Jin

et al. 2010

Clinical Cancer Research

139

135

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Purpose: Nasopharyngeal carcinoma is prevalent in southern China and Southeast Asia, with distinct geographic and ethnic distribution. One candidate susceptibility locus has been identified at 4p11-14, with the associated candidate gene(s) not identified yet. This study investigated the role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in nasopharyngeal carcinoma pathogenesis.Experimental Design: UCHL1 expression and methylation were examined in nasopharyngeal carcinoma. Furthermore, the mechanism of its tumor-suppressive function was elucidated in nasopharyngeal carcinoma cells.Results: Through genomewide expression profiling, we identified UCHL1, a 4p14 gene normally expressed in normal upper respiratory tract tissues, being silenced in all nasopharyngeal carcinoma cell lines. Its silencing is mediated by CpG methylation because UCHL1 promoter methylation was detected in all silenced cell lines, and pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. UCHL1 methylation was also frequently detected in primary tumors but only weakly detected in few normal nasopharyngeal tissues, indicating that the methylation-mediated silencing of UCHL1 is important in nasopharyngeal carcinoma pathogenesis. Ectopic UCHL1 expression dramatically inhibited the growth of nasopharyngeal carcinoma cells through promoting tumor cell apoptosis. We further found that UCHL1 formed a complex with p53/p14 ARF /Mdm2 p53 binding protein homolog (mouse), MDM2 and activated the p53 signaling pathway. UCHL1 expression extended p53 and p14ARF protein half-life and shortened MDM2 protein half-life. Conclusions:These results indicate that UCHL1 could deubiquitinate p53 and p14 ARF and ubiquitinate MDM2 for p53 stabilization to promote p53 signaling, thus involved in nasopharyngeal carcinoma pathogenesis, whereas it is frequently silenced in this tumor.

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Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor UCHL1 Forms a Complex with p53/MDM2/ARF to Promote p53 Signaling and Is Frequently Silenced in Nasopharyngeal Carcinoma

Tao

Jin

et al. 2010

Clinical Cancer Research

139

135

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“…Squares indicate the protein spots that were differentially expressed between sham and MCAO-operated groups. including cell differentiation, stress response, and apoptosis [21]. UCH-L1 attenuates neuronal cell death from oxidative stress, and a UCH-L1 decrease induces neuronal degeneration in neurodegenerative disease [5,21].…”

Section: Discussionmentioning

confidence: 99%

“…including cell differentiation, stress response, and apoptosis [21]. UCH-L1 attenuates neuronal cell death from oxidative stress, and a UCH-L1 decrease induces neuronal degeneration in neurodegenerative disease [5,21]. The reduction of UCH-L1 induces a malfunction of the de-ubiquitination and ubiquitination mechanisms, sequentially leading to apoptosis [25].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Focal Cerebral Ischemic Injury in Male Rats

Koh

2010

J. Vet. Med. Sci.

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ABSTRACT. The present study identified the proteins that are differentially expressed during ischemic brain injury. Adult male rats were performed a middle cerebral artery occlusion (MCAO) to induce cerebral ischemia, and brains were collected at 24 hr after MCAO. Protein analysis was performed on the cerebral cortex using two-dimensional gel electrophoresis. Protein spots with a greater than 3 fold change in intensity between the sham and MCAO groups were identified by mass spectrometry. Among these proteins, 60 kDa heat shock protein, dehydropyrimidinase-related protein 2, t-complex protein 1, and Rho GDP dissociation inhibitor levels were significantly increased in MCAO group compared to those of the sham group. In contrast, thioredoxin, peroxiredoxin-2, stathmin, ubiquitin carboxyterminal hydrolase L1, guanine nucleotide-binding protein , pyridoxal-5'-phosphate phosphatase, and apoplipoprotein A-I levels were significantly decreased in MCAO group. These results suggest that cerebral ischemia induces neuronal cells death by changing expression levels of several proteins. Neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and stroke are a major cause of adult disability and mortality. Among these disorders, stroke is a serious cerebrovascular disorder and the most common cause of death. A previous study demonstrated that cerebral ischemia in an experimental stroke model involves apoptotic and survival signaling pathways and leads to neuronal cells death [24]. Oxidative stress, metabolic compromise, and mitochondrial dysfunction may trigger neuronal apoptosis in neurodegenerative disorders [17]. The mechanisms of neuronal cell death are very complex and vague. At present, little is known about the changes in protein expression in damaged brain region during ischemic injury. The purpose of this study was to investigate these changes in expression in the cerebral cortex following ischemic brain injury. MATERIALS AND METHODSExperimental animals: Male Sprague-Dawley rats (225-250 g, n=40) were purchased from Samtako Co. (Animal Breeding Center, Osan, Korea) and were randomly divided into two groups, sham-operated group and middle cerebral artery occlusion (MCAO)-operated group (n=20 per group). Animals were maintained under controlled temperature (25C) and lighting (14L:10D), and allowed free access to food and water. All animal experiments were carried out in accordance with the Guide for care and use of laboratory animals, and use of Gyeongsang National University.Middle cerebral artery occlusion: The MCAO model was prepared following the previously described method of intra-luminal vascular occlusion [16]. Animals were anesthetized with sodium pentobarbital (100 mg/kg). The right common carotid artery, internal carotid artery, and external carotid artery were exposed through a midline cervical incision. A 4/0 monofilament nylon was inserted from the external carotid artery into the lumen of the internal carotid artery until it obstructed the origin of the middle cerebral artery. At ...

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“…When GAPDH was used as a control, no changes in TH and NET mRNA were found in the SG of mice 1 wk after ischemia-reperfusion (32). PGP9.5 gene expression can be downregulated by oxidative stress (41), and ROS generation is increased during ischemia-reperfusion injury (36) and can be induced by ANG II (49). The latter mechanism may contribute to the observed twofold decrease of PGP9.5 mRNA in the SG at 12 wk post-MI, since circulating plasma levels of ANG II are persistently elevated in rats post-MI (23).…”

Section: Time Course Of Th Net and Pgp95 Expressionmentioning

confidence: 99%

Cardiac sympathetic innervation and PGP9.5 expression by cardiomyocytes after myocardial infarction: effects of central MR blockade

Drobysheva

Ahmad

White

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Drobysheva A, Ahmad M, White R, Wang H, Leenen FH. Cardiac sympathetic innervation and PGP9.5 expression by cardiomyocytes after myocardial infarction: effects of central MR blockade. Am J Physiol Heart Circ Physiol 305: H1817-H1829, 2013. First published October 11, 2013; doi:10.1152/ajpheart.00445.2013.-Central mechanisms involving mineralocorticoid receptor (MR) activation contribute to an increase in sympathetic tone after myocardial infarction (MI). We hypothesized that this central mechanism also contributes to cardiac sympathetic axonal sprouting and that central MR blockade reduces cardiac sympathetic hyperinnervation post-MI. Post-MI, tyrosine hydroxylase (TH) and norepinephrine transporter protein content in the noninfarcted base of the heart remained unaltered. In contrast, protein gene product (PGP)9.5 protein was increased twofold in the base of the heart and sixfold in the peri-infarct area at 1 wk post-MI and was associated with increased ubiquitin expression. These changes persisted to a lesser extent at 4 wk post-MI and were no longer present at 12 wk. Cardiac myocytes rather than sympathetic axons were the main source of this elevated PGP9.5 expression. At 7-10 days post-MI, in the peri-infarct area, sympathetic hyperinnervation was observed with a fourfold increase in growth-associated protein 43, a twofold increase in TH, and a 50% increase in PGP9.5-positive fibers compared with the epicardial side of the left ventricle in sham rats. Central infusion of the MR blocker eplerenone markedly attenuated these increases in nerve densities but did not affect overall cardiac PGP9.5 and ubiquitin protein overexpression. We conclude that central MR activation contributes to sympathetic hyperinnervation, possibly by decreasing cardiac sympathetic activity post-MI, or by affecting other mechanisms, such as the expression of nerve growth factor. Marked PGP9.5 expression occurs in cardiomyocytes early post-MI, which may contribute to the increase in ubiquitin. myocardial infarction; cardiac sympathetic hyperinnervation; brain mineralocorticoid receptors; eplerenone; ubiquitin; protein gene product 9.5 CARDIAC REMODELING after myocardial infarction (MI) affects both infarcted and noninfarcted areas of the heart and contributes to the impairment of ventricular performance (19,43,44). Cardiac sympathetic hyperactivity enhances maladaptive cardiac remodeling post-MI and plays a major role in the development of chronic heart failure (CHF) (5, 31). In humans with mild CHF, there is a selective increase in cardiac sympathetic activity, which is followed by augmented sympathetic outflow to skeletal muscle and the kidneys as CHF progresses (16,38). In rats, direct recordings from cardiac sympathetic nerves demonstrate that cardiac sympathetic nerve activity (CSNA) increased twofold within hours after MI (40). In conscious sheep, CSNA was significantly increased by the second hour post-MI and remained elevated for at least 1 wk (14).Increased CSNA may also contribute to the development of cardiac sympathetic hyperi...

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Oxidative stress regulated expression of Ubiquitin Carboxyl-terminal Hydrolase-L1: Role in cell survival

Cited by 62 publications

References 55 publications

The Tumor Suppressor UCHL1 Forms a Complex with p53/MDM2/ARF to Promote p53 Signaling and Is Frequently Silenced in Nasopharyngeal Carcinoma

The Tumor Suppressor UCHL1 Forms a Complex with p53/MDM2/ARF to Promote p53 Signaling and Is Frequently Silenced in Nasopharyngeal Carcinoma

Proteomic Analysis of Focal Cerebral Ischemic Injury in Male Rats

Cardiac sympathetic innervation and PGP9.5 expression by cardiomyocytes after myocardial infarction: effects of central MR blockade

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