TY  - JOUR
AU  - Mikulak, Joanna
AU  - Negrini, Sara
AU  - Lazić, Andrijana
AU  - D'Alessandro, Rosalba
AU  - Mavilio, Domenico
AU  - Meldolesi, Jacopo
PY  - 2012
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/581
AB  - L1 cell adhesion molecule (L1CAM), an adhesion/signaling protein encoded by a gene target of the transcription repressor RE-1-Silencing Transcription factor (REST), is expressed in two alternatively spliced isoforms. The full-length isoform, typical of low-REST neural cells, plays key roles in survival/migration, outgrowth/fasciculation/regeneration of axons, synaptic plasticity; the isoform missing two mini-exons, abundant in a few high-REST non-neural cells, maintains some effect on migration and proliferation. To investigate whether and how L1CAM alternative splicing depends on REST we used neural cell models expressing low or high levels of REST (PC12, SH-SY5Y, differentiated NT2/D1 and primary neurons transduced or not with REST). The short isoform was found to rise when the low-REST levels of neural cells were experimentally increased, while the full-length isoform increased in high-REST cells when the repressor tone was attenuated. These results were due to Nova2, a neural cell-specific splicing factor shown here to be repressed by REST. REST control of L1CAM occurs therefore by two mechanisms, transcription and alternative splicing. The splicing mechanism, affecting not only L1CAM but all Nova2 targets (similar to 7% of brain-specific splicing, including the mRNAs of other adhesion and synaptic proteins) is expected to be critical during development and important also for the structure and function of mature neural cells.
PB  - Wiley, Hoboken
T2  - Journal of Neurochemistry
T1  - Dual REST-dependence of L1CAM: from gene expression to alternative splicing governed by Nova2 in neural cells
EP  - 709
IS  - 5
SP  - 699
VL  - 120
DO  - 10.1111/j.1471-4159.2011.07626.x
ER  - 

@article{
author = "Mikulak, Joanna and Negrini, Sara and Lazić, Andrijana and D'Alessandro, Rosalba and Mavilio, Domenico and Meldolesi, Jacopo",
year = "2012",
abstract = "L1 cell adhesion molecule (L1CAM), an adhesion/signaling protein encoded by a gene target of the transcription repressor RE-1-Silencing Transcription factor (REST), is expressed in two alternatively spliced isoforms. The full-length isoform, typical of low-REST neural cells, plays key roles in survival/migration, outgrowth/fasciculation/regeneration of axons, synaptic plasticity; the isoform missing two mini-exons, abundant in a few high-REST non-neural cells, maintains some effect on migration and proliferation. To investigate whether and how L1CAM alternative splicing depends on REST we used neural cell models expressing low or high levels of REST (PC12, SH-SY5Y, differentiated NT2/D1 and primary neurons transduced or not with REST). The short isoform was found to rise when the low-REST levels of neural cells were experimentally increased, while the full-length isoform increased in high-REST cells when the repressor tone was attenuated. These results were due to Nova2, a neural cell-specific splicing factor shown here to be repressed by REST. REST control of L1CAM occurs therefore by two mechanisms, transcription and alternative splicing. The splicing mechanism, affecting not only L1CAM but all Nova2 targets (similar to 7% of brain-specific splicing, including the mRNAs of other adhesion and synaptic proteins) is expected to be critical during development and important also for the structure and function of mature neural cells.",
publisher = "Wiley, Hoboken",
journal = "Journal of Neurochemistry",
title = "Dual REST-dependence of L1CAM: from gene expression to alternative splicing governed by Nova2 in neural cells",
pages = "709-699",
number = "5",
volume = "120",
doi = "10.1111/j.1471-4159.2011.07626.x"
}

Mikulak, J., Negrini, S., Lazić, A., D'Alessandro, R., Mavilio, D.,& Meldolesi, J.. (2012). Dual REST-dependence of L1CAM: from gene expression to alternative splicing governed by Nova2 in neural cells. in Journal of Neurochemistry
Wiley, Hoboken., 120(5), 699-709.
https://doi.org/10.1111/j.1471-4159.2011.07626.x

Mikulak J, Negrini S, Lazić A, D'Alessandro R, Mavilio D, Meldolesi J. Dual REST-dependence of L1CAM: from gene expression to alternative splicing governed by Nova2 in neural cells. in Journal of Neurochemistry. 2012;120(5):699-709.
doi:10.1111/j.1471-4159.2011.07626.x .

Mikulak, Joanna, Negrini, Sara, Lazić, Andrijana, D'Alessandro, Rosalba, Mavilio, Domenico, Meldolesi, Jacopo, "Dual REST-dependence of L1CAM: from gene expression to alternative splicing governed by Nova2 in neural cells" in Journal of Neurochemistry, 120, no. 5 (2012):699-709,
https://doi.org/10.1111/j.1471-4159.2011.07626.x . .

TY  - JOUR
AU  - Tomasoni, Romana
AU  - Negrini, Sara
AU  - Fiordaliso, Stefania
AU  - Lazić, Andrijana
AU  - Tkatch, Tatiana
AU  - Mondino, Anna
AU  - Meldolesi, Jacopo
AU  - D'Alessandro, Rosalba
PY  - 2011
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/480
AB  - The RE-1-specific silencing transcription factor (REST or NRSF) is a transcription repressor that orchestrates differentiation and also operates in differentiated neurons and neurosecretory cells (neural cells). Its role in proliferation has been investigated so far only in rapidly growing tumors, with conflicting results: suppression in non-neural tumors, stimulation in medulloblastomas. Working with two clones of chromaffin-neuronal PC12 cells, which express different levels of REST, and using genetic complementation and knockdown approaches, we show that REST also promotes proliferation in differentiated neural cells. Mechanistically, this occurs by a signaling pathway involving REST, the GTPase-activating protein tuberin (TSC2) and the transcription co-factor beta-catenin. In PC12 cells, raised expression of REST correlates with reduced TSC2 levels, nuclear accumulation and co-transcriptional activation of beta-catenin, and increased expression of its target oncogenes Myc and Ccnd1, which might account for the proliferation advantage and the distinct morphology. Rest transcription is also increased, unveiling the existence of a self-sustaining, feed-forward REST-TSC2-beta-catenin signaling loop that is also operative in another neural cell model, NT2/D1 cells. Transfection of REST, knockdown of TSC2 or forced expression of active beta-catenin recapitulated the biochemical, functional and morphological properties of the high-expressing REST clone in wild-type PC12 cells. Upregulation of REST promoted proliferation and phenotypic changes, thus hindering neurosecretion. The new REST-TSC2-beta-catenin signaling paradigm might have an important role in various aspects of neural cell physiology and pathology, including the regulation of proliferation and neurosecretion.
PB  - Company Biologists Ltd, Cambridge
T2  - Journal of Cell Science
T1  - A signaling loop of REST, TSC2 and beta-catenin governs proliferation and function of PC12 neural cells
EP  - 3186
IS  - 18
SP  - 3174
VL  - 124
DO  - 10.1242/jcs.087551
ER  - 

@article{
author = "Tomasoni, Romana and Negrini, Sara and Fiordaliso, Stefania and Lazić, Andrijana and Tkatch, Tatiana and Mondino, Anna and Meldolesi, Jacopo and D'Alessandro, Rosalba",
year = "2011",
abstract = "The RE-1-specific silencing transcription factor (REST or NRSF) is a transcription repressor that orchestrates differentiation and also operates in differentiated neurons and neurosecretory cells (neural cells). Its role in proliferation has been investigated so far only in rapidly growing tumors, with conflicting results: suppression in non-neural tumors, stimulation in medulloblastomas. Working with two clones of chromaffin-neuronal PC12 cells, which express different levels of REST, and using genetic complementation and knockdown approaches, we show that REST also promotes proliferation in differentiated neural cells. Mechanistically, this occurs by a signaling pathway involving REST, the GTPase-activating protein tuberin (TSC2) and the transcription co-factor beta-catenin. In PC12 cells, raised expression of REST correlates with reduced TSC2 levels, nuclear accumulation and co-transcriptional activation of beta-catenin, and increased expression of its target oncogenes Myc and Ccnd1, which might account for the proliferation advantage and the distinct morphology. Rest transcription is also increased, unveiling the existence of a self-sustaining, feed-forward REST-TSC2-beta-catenin signaling loop that is also operative in another neural cell model, NT2/D1 cells. Transfection of REST, knockdown of TSC2 or forced expression of active beta-catenin recapitulated the biochemical, functional and morphological properties of the high-expressing REST clone in wild-type PC12 cells. Upregulation of REST promoted proliferation and phenotypic changes, thus hindering neurosecretion. The new REST-TSC2-beta-catenin signaling paradigm might have an important role in various aspects of neural cell physiology and pathology, including the regulation of proliferation and neurosecretion.",
publisher = "Company Biologists Ltd, Cambridge",
journal = "Journal of Cell Science",
title = "A signaling loop of REST, TSC2 and beta-catenin governs proliferation and function of PC12 neural cells",
pages = "3186-3174",
number = "18",
volume = "124",
doi = "10.1242/jcs.087551"
}

Tomasoni, R., Negrini, S., Fiordaliso, S., Lazić, A., Tkatch, T., Mondino, A., Meldolesi, J.,& D'Alessandro, R.. (2011). A signaling loop of REST, TSC2 and beta-catenin governs proliferation and function of PC12 neural cells. in Journal of Cell Science
Company Biologists Ltd, Cambridge., 124(18), 3174-3186.
https://doi.org/10.1242/jcs.087551

Tomasoni R, Negrini S, Fiordaliso S, Lazić A, Tkatch T, Mondino A, Meldolesi J, D'Alessandro R. A signaling loop of REST, TSC2 and beta-catenin governs proliferation and function of PC12 neural cells. in Journal of Cell Science. 2011;124(18):3174-3186.
doi:10.1242/jcs.087551 .

Tomasoni, Romana, Negrini, Sara, Fiordaliso, Stefania, Lazić, Andrijana, Tkatch, Tatiana, Mondino, Anna, Meldolesi, Jacopo, D'Alessandro, Rosalba, "A signaling loop of REST, TSC2 and beta-catenin governs proliferation and function of PC12 neural cells" in Journal of Cell Science, 124, no. 18 (2011):3174-3186,
https://doi.org/10.1242/jcs.087551 . .