Glioblastoma is the most common and malignant brain tumor in adults. Glioblastoma is highly resistant to chemotherapy and radiotherapy. So far, there has been no successful treatment. Recent studies revealed a strong correlation between glioblastoma tumorigenicity and the aberrant expression of REST, the main repressor of neural stem cell differentiation [1].
The fate of the REST inside cells is mainly regulated by ubiquitylation. The primary protecting role is played by telomeric factor TRF2 that forms a complex with REST and protects it from ubiquitylation and therefore from proteasomal degradation [2]. TRF2 also forms the core of the shelterin complex that shields chromosome ends against unwanted end-joining and DNA repair machinery. REST indirectly regulates TRF2 expression; thus, it affects shelterin complex formation [3]. REST TRF2 complex disruption is a promising target of molecular therapy that will provide a dual effect on cancer stem cells.
Here, we have investigated in cell localization of REST and TRF2, and we have observed the formation of REST-TRF2 complex directly in the cell nucleus using Proximity ligation assay. We have determined the structure of transcription factor REST using cryo-electron microscopy single-particle reconstruction. A better understanding of the REST-TRF2 complex will provide valuable knowledge in development of drugs against glioblastoma.
1. D. Zhang, Y. Li, R. Wang, Y. Li, P. Shi, Z. Kan, X. Pang, Int. J. Mol. Sci., 17, (2016), 664. 2. Z. Huang, and S. Bao, FEBS letters, 586, (2012), 1602. 3. P. Ovando-Roche, J.S.L. Yu, S. Testori, C. Ho, W. Cui, Stem Cells, 32, (2014), 2111.
Návaznosti
GA19-18226S, projekt VaV
Název: Kritické interakce neuronového transkripčního faktoru REST se stabilizátorem TRF2: biofyzikální implikace pro návrh léčiv glioblastomu
Investor: Grantová agentura ČR, Kritické interakce neuronového transkripčního faktoru REST se stabilizátorem TRF2: biofyzikální implikace pro návrh léčiv glioblastomu
LM2018127, velká výzkumná infrastruktura
Název: Czech Infrastructure for Integrative Structural Biology (Akronym: CIISB)
Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Czech Infrastructure for Integrative Structural Biology
LM2018127, velká výzkumná infrastruktura
Název: Česká infrastruktura pro integrativní strukturní biologii (Akronym: CIISB)
Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Czech Infrastructure for Integrative Structural Biology
LM2018129, velká výzkumná infrastruktura
Název: National research infrastructure for biological and medical imaging
Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, National research infrastructure for biological and medical imaging
LM2018129, velká výzkumná infrastruktura
Název: Národní infrastruktura pro biologické a medicínské zobrazování Czech-BioImaging
Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, National research infrastructure for biological and medical imaging
LTAUSA19024, projekt VaV
Název: Role regulace transkripce při chemoterapeutické rezistenci glioblastomu: in vitro a in vivo validace cíle pro molekulární terapii
Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Role regulace transkripce při chemoterapeutické rezistenci glioblastomu: in vitro a in vivo validace cíle pro molekulární terapii, INTER-ACTION
MUNI/A/1556/2021, interní kód MU
Název: Specifický výzkum v oblastech funkční genomiky a proteomiky (Akronym: SV-FGP)
Investor: Masarykova univerzita, Specifický výzkum v oblastech funkční genomiky a proteomiky
BROM, Tomáš, Tomáš JANOVIČ, Pavel VEVERKA, Martin STOJASPAL a Ctirad HOFR. Critical interactions of neuronal transcription factor REST with stabilizer TRF2. 2022.
@proceedings{1843617, author = {Brom, Tomáš and Janovič, Tomáš and Veverka, Pavel and Stojaspal, Martin and Hofr, Ctirad}, language = {eng}, title = {Critical interactions of neuronal transcription factor REST with stabilizer TRF2}, url = {https://www.xray.cz/setkani/abst2022/519.htm}, year = {2022} }
TY - CONF ID - 1843617 AU - Brom, Tomáš - Janovič, Tomáš - Veverka, Pavel - Stojaspal, Martin - Hofr, Ctirad PY - 2022 TI - Critical interactions of neuronal transcription factor REST with stabilizer TRF2 UR - https://www.xray.cz/setkani/abst2022/519.htm N2 - Glioblastoma is the most common and malignant brain tumor in adults. Glioblastoma is highly resistant to chemotherapy and radiotherapy. So far, there has been no successful treatment. Recent studies revealed a strong correlation between glioblastoma tumorigenicity and the aberrant expression of REST, the main repressor of neural stem cell differentiation [1].
The fate of the REST inside cells is mainly regulated by ubiquitylation. The primary protecting role is played by telomeric factor TRF2 that forms a complex with REST and protects it from ubiquitylation and therefore from proteasomal degradation [2]. TRF2 also forms the core of the shelterin complex that shields chromosome ends against unwanted end-joining and DNA repair machinery. REST indirectly regulates TRF2 expression; thus, it affects shelterin complex formation [3]. REST TRF2 complex disruption is a promising target of molecular therapy that will provide a dual effect on cancer stem cells.
Here, we have investigated in cell localization of REST and TRF2, and we have observed the formation of REST-TRF2 complex directly in the cell nucleus using Proximity ligation assay. We have determined the structure of transcription factor REST using cryo-electron microscopy single-particle reconstruction. A better understanding of the REST-TRF2 complex will provide valuable knowledge in development of drugs against glioblastoma.
1. D. Zhang, Y. Li, R. Wang, Y. Li, P. Shi, Z. Kan, X. Pang, Int. J. Mol. Sci., 17, (2016), 664. 2. Z. Huang, and S. Bao, FEBS letters, 586, (2012), 1602. 3. P. Ovando-Roche, J.S.L. Yu, S. Testori, C. Ho, W. Cui, Stem Cells, 32, (2014), 2111.
ER -
BROM, Tomáš, Tomáš JANOVIČ, Pavel VEVERKA, Martin STOJASPAL a Ctirad HOFR. \textit{Critical interactions of neuronal transcription factor REST with stabilizer TRF2}. 2022.