UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27

Mishra, Amit; Godavarthi, Swetha K.; Jana, Nihar Ranjan

doi:10.1016/j.nbd.2009.06.010

Cited by 79 publications

(69 citation statements)

References 48 publications

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“…Absence of E6AP enhances the growth of mouse embryo fibroblasts E6AP has been linked to a number of cell cycle regulators, including p53, PML, RING1B and the cyclin-dependent kinase inhibitor p27 (Mishra et al, 2009). It was therefore of interest to examine the effect of E6AP deficiency on the growth rate of primary early passage MEFs.…”

Section: Resultsmentioning

confidence: 99%

E6AP is required for replicative and oncogene-induced senescence in mouse embryo fibroblasts

Levav-Cohen¹,

Wolyniec

Alsheich-Bartok³

et al. 2011

Oncogene

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Section: Resultsmentioning

confidence: 99%

E6AP is required for replicative and oncogene-induced senescence in mouse embryo fibroblasts

Levav-Cohen¹,

Wolyniec

Alsheich-Bartok³

et al. 2011

Oncogene

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“…Although Ube3a overexpression is known to promote UPSmediated degradation of transfected mHtt in cultured cells (54,55), how Ube3a expression levels impact HD pathology remains unclear. In our studies, we provide in vivo evidence that Ube3a levels can reduce mHtt aggregation in the HD KI mouse brain.…”

Section: Discussionmentioning

confidence: 99%

Differential ubiquitination and degradation of huntingtin fragments modulated by ubiquitin-protein ligase E3A

Bhat

Yan

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

100

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Ubiquitination of misfolded proteins, a common feature of many neurodegenerative diseases, is mediated by different lysine (K) residues in ubiquitin and alters the levels of toxic proteins. In Huntington disease, polyglutamine expansion causes N-terminal huntingtin (Htt) to misfold, inducing neurodegeneration. Here we report that shorter N-terminal Htt fragments are more stable than longer fragments and find differential ubiquitination via K63 of ubiquitin. Aging decreases proteasome-mediated Htt degradation, at the same time increasing K63-mediated ubiquitination and subsequent Htt aggregation in HD knock-in mice. The association of Htt with the K48-specific E3 ligase, Ube3a, is decreased in aged mouse brain. Overexpression of Ube3a in HD mouse brain reduces K63-mediated ubiquitination and Htt aggregation, enhancing its degradation via the K48 ubiquitin-proteasome system. Our findings suggest that aging-dependent Ube3a levels result in differential ubiquitination and degradation of Htt fragments, thereby contributing to the age-related neurotoxicity of mutant Htt.misfolding | proteolysis H untington disease (HD) is caused by an autosomal-dominant mutation in the HD gene that results in an expansion of CAG triplets (n > 35), leading to an expansion of polyglutamine (polyQ) repeats in the N-terminal region of huntingtin (Htt), as well as protein misfolding and aggregation (1, 2). Although Htt is ubiquitously expressed in the brain and body, mutant Htt (mHtt) causes selective neurodegeneration that preferentially occurs in the striatum and extends to other brain regions as disease progresses (1,3,4). The selective neurodegeneration in HD is apparently associated with the age-dependent accumulation of misfolded Htt in neuronal cells, which results in the formation of aggregates in the brain. Brains from patients with HD show Htt aggregates in neuronal nuclei and processes, which are formed by N-terminal fragments of mHtt (5, 6). The N-terminal fragments of mHtt in the nucleus can dysregulate gene transcription, and mHtt in neuronal processes can affect intracellular trafficking and neuron transmitter release (7-10). Similarly, most age-dependent neurodegenerative diseases, including Alzheimer's disease and Parkinson disease, show increased accumulation of misfolded proteins in neuronal cells with age (11, 12). Thus, understanding how mHtt accumulates in the brain will shed light on the mechanisms for several age-dependent neurodegenerative diseases.The accumulation of misfolded proteins is caused largely by impaired clearance of these proteins in aged neurons (13). Previous studies showed that the ubiquitin-proteasome system (UPS) and the autophagic pathway can degrade mHtt (14-20). Indeed, the neuronal aggregates seen in HD and other neurodegenerative diseases are found to contain ubiquitinated proteins (5, 6). Although these ubiquitin-enriched aggregates are a hallmark of HD and other neurodegenerative diseases, how they are linked to the development of neurodegeneration remains unclear.Previous studies revealed ...

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“…Although ubiquitously expressed, Ube3a localizes to the nucleus where it serves as a transcriptional coactivator and plays a role in the chromosome segregation (Nawaz et al 1999;Singhmar and Kumar 2011). Nuclear association is also expected due to other Ube3a targets, including p53, p27, or HHR23A (Jiang et al 1998;Kumar et al 1999;Mishra and Jana 2008;Mishra et al 2009). However, the potential role for up-regulation of nuclear associated Ube3a is yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Activity-dependent changes in MAPK activation in the Angelman Syndrome mouse model

et al. 2014

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Angelman Syndrome (AS) is a devastating neurological disorder caused by disruption of the maternal UBE3A gene. Ube3a protein is identified as an E3 ubiquitin ligase that shows neuron-specific imprinting. Despite extensive research evaluating the localization and basal expression profiles of Ube3a in mouse models, the molecular mechanisms whereby Ube3a deficiency results in AS are enigmatic. Using in vitro and in vivo systems we show dramatic changes in the expression of Ube3a following synaptic activation. In primary neuronal culture, neuronal depolarization was found to increase both nuclear and cytoplasmic Ube3a levels. Analogous up-regulation in maternal and paternal Ube3a expression was observed in Ube3a-YFP reporter mice following fear conditioning. Absence of Ube3a led to deficits in the activity-dependent increases in ERK1/2 phosphorylation, which may contribute to reported deficits in synaptic plasticity and cognitive function in AS mice. Taken together, our findings provide novel insight into the regulation of Ube3a by synaptic activity and its potential role in kinase regulation.

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UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27

Cited by 79 publications

References 48 publications

E6AP is required for replicative and oncogene-induced senescence in mouse embryo fibroblasts

E6AP is required for replicative and oncogene-induced senescence in mouse embryo fibroblasts

Differential ubiquitination and degradation of huntingtin fragments modulated by ubiquitin-protein ligase E3A

Activity-dependent changes in MAPK activation in the Angelman Syndrome mouse model

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