Abstract
The UBE3A gene codes for a protein with two known functions, a ubiquitin E3-ligase which catalyzes ubiquitin binding to substrate proteins and a steroid hormone receptor coactivator. UBE3A is most famous for its critical role in neuronal functioning. Lack of UBE3A protein expression leads to Angelman syndrome (AS), while its overexpression is associated with autism. In spite of extensive research, our understanding of UBE3A roles is still limited. We investigated the cellular and molecular effects of Ube3a deletion in mouse embryonic fibroblasts (MEFs) and Angelman syndrome (AS) mouse model hippocampi. Cell cultures of MEFs exhibited enhanced proliferation together with reduced apoptosis when Ube3a was deleted. These findings were supported by transcriptome and proteome analyses. Furthermore, transcriptome analyses revealed alterations in mitochondria-related genes. Moreover, an analysis of adult AS model mice hippocampi also found alterations in the expression of apoptosis- and proliferation-associated genes. Our findings emphasize the role UBE3A plays in regulating proliferation and apoptosis and sheds light into the possible effects UBE3A has on mitochondrial involvement in governing this balance.
Highlights
The Ubiquitin protein ligase E3A (UBE3A) gene that encodes for the ubiquitin E3-ligase protein UBE3A is located in the q11–q13 region of chromosome 15 in humans and at 28.65 cm of chromosome 7 in mice
After 48 h, the mean fluorescence intensity of the Ube3a−/− mouse embryonic fibroblasts (MEFs) declined by 3.39-fold, while the fluorescence intensity of Ube3a+/+ MEFs declined only by 2.53-fold (t(2) = 11.05, p < 0.01 post-hoc Bonferroni corrected comparison) (Figure 1B,C)
Previous studies showed that a low BAX/BCL-2 ratio is typically associated with antiapoptotic properties, while a high BAX/BCL-2 ratio is found in cells that are more sensitive to apoptosis
Summary
The UBE3A gene that encodes for the ubiquitin E3-ligase protein UBE3A is located in the q11–q13 region of chromosome 15 in humans and at 28.65 cm of chromosome 7 in mice. It can act as a hormone-dependent coactivator for nuclear hormone receptors, such as androgen receptors (AR), estrogen receptors (ER), and some auxiliary regulatory proteins [5]. In order to understand the consequences of UBE3A deletion in Angelman syndrome, a mouse model that carries the maternal deletion of exon 2 of the Ube3a gene [21] was generated. This model has been shown to recapitulate most phenotypes seen in AS patients, such as impaired motor function, seizures, and cognitive and hippocampal-dependent long-term memory deficits, making these models an efficient tool for investigating AS [21,22,23]
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