A signaling loop of REST, TSC2 and beta-catenin governs proliferation and function of PC12 neural cells
2011
Authors
Tomasoni, RomanaNegrini, Sara
Fiordaliso, Stefania
Lazić, Andrijana
Tkatch, Tatiana
Mondino, Anna
Meldolesi, Jacopo
D'Alessandro, Rosalba
Article (Published version)
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Show full item recordAbstract
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.
Keywords:
PC12 cells / NT2/D1 cells / Neurosecretion / Neural cell differentiation / Gene expressionSource:
Journal of Cell Science, 2011, 124, 18, 3174-3186Publisher:
- Company Biologists Ltd, Cambridge
Funding / projects:
- Telethon [GGGP09066]
- AIRC
- Studying signal transduction pathways and epigenetic mechanisms that control human SOX genes expression: further insight into their roles in cell fate determination and differentiation (RS-MESTD-Basic Research (BR or ON)-173051)
- Izučavanje regulacije ekspresije i funkcije humanih SOX gena (RS-MESTD-MPN2006-2010-143028)
DOI: 10.1242/jcs.087551
ISSN: 0021-9533
PubMed: 21868364
WoS: 000294821300014
Scopus: 2-s2.0-80054011480
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Institution/Community
Institut za molekularnu genetiku i genetičko inženjerstvoTY - 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 . .