Signaling and checkpoints of cell cycle. PI: Neus Agell Jané

Presentation

The general objective of the group is to investigate the signal transduction pathways that regulate the progression of the cell cycle and its control mechanisms (checkpoints), as well as to analyze the implication of their alterations in oncogenesis. In relation to this general objective, in recent years we have developed the following lines of research:

  1. New strategies to inhibit oncogenic KRAS.
  2. Replicative stress: response of untransformed cells versus tumor cells.

The group is also part of the IDIBAPS Research Institute within the "Intracellular Compartments and Signaling" research team in the Oncology and Hematology area:

http://www.idibaps.org/recerca/309/compartiments-intracel%C2%B7lulars-i-senyalitzacio

 

Dra. Neus Agell Jané
Full Professor of Cell Biology
neusagell@ub.edu


Dra. Montserrat Jaumot Pijoan
Associate Professor
mjaumot@ub.edu


Dra. Sònia Brun Lozano
Higher Technique in Cell Biology
soniabrun@ub.edu


Baraa Abuasaker
Pre-doctoral student, UB Pre-doc Scholarship
babuasaker@ub.edu


Jesús Daniel Gómez Zepeda
Pre-doctoral student, UB Pre-doc Scholarship
jgomezze7@alumnes.ub.edu


Fernando Unzueta Payeras
Pre-doctoral student, FPU Scholarship (MINECO)
f.unzueta@ub.edu


Alejandro Rosell Jiménez
Master's student in Biomedicine
aroselji7@alumnes.ub.edu

 

Laia Peralba Parada
Degree student in Biomedical Sciences
lperalpa7@alumnes.ub.edu


Laia Rocher Cujó
Degree Student in Biomedical Sciences
lrochecu18@alumnes.ub.edu

  • New strategies to inhibit oncogenic KRAS

Ras proteins are small GTPases that regulate signal transduction pathways that control cell proliferation, differentiation, survival, and apoptosis. Oncogenic mutations of the KRAS isoform are very common in colorectal, pancreatic, and lung cancers. Unfortunately, no good inhibitors of KRAS function have yet been found that can be used in therapy. In order to deepen the knowledge of the regulation of KRAS and search for strategies to inhibit its oncogenic action, our group: on the one hand, investigates the role of KRAS phosphorylation at serine 181; and on the other, it identifies proteins that interact with KRAS and regulate its function, until now not described. Summarizing, we have shown that the phosphorylation of KRAS regulates its oncogenic activity, and that calmodulin and hnRNPA2 proteins specifically bind to KRAS. Moreover, calmodulin inhibits the phosphorylation of KRAS at serine 181, and thus modulates the functionality of the non-oncogenic and oncogenic forms; and hnRNPA2 interacts better with the phosphorylated form of KRAS and favours its signalling in adenocarcinoma cells of the pancreas.

  • Replicative stress: response of untransformed cells versus tumour cells

Genomic instability is a hallmark of tumour cells, and DNA replication is the most vulnerable cell cycle event to genomic instability. Replicative stress plays an important role in oncogenesis, but at the same time it could become a good target in cancer therapy. That is why our group investigates the responses to replicative stress of tumour cells versus non-transformed cells, whether it is induced by nucleotide depletion, DNA damage, or by overexpression of an oncogene such as KRAS. Our results demonstrate that after severe replicative stress, the non-transformed cells go into senescence while most tumour cells are able to recover and continue to proliferate but acquiring alterations in the genome.

  • New KRAS interactors relevant for its oncogenic activity and effect of replication stress in transcriptional activity

Ministerio de Ciencia, Innovación y Universidades
2020-2023
Investigador principal: Neus Agell Jané

  • La fosforilación de K-Ras, su interacción con calmodulina, y la respuesta al estrés replicativo, en la progresión del cáncer colorectal y en el diseño de nuevas terapias. SAF2016-76239-R

30/12/2016 al 29/12/2019
PI: Neus Agell Jané

For more information for PI publications click in the link:
ORCID: https://orcid.org/0000-0002-1205-6074

 

Pelletier J, Riaño-Canalias F, Almacellas E, Mauvezin C, Samino S, Feu S, Menoyo S, Domostegui A, Garcia-Cajide M, Salazar R, Cortés C, Marcos R, Tauler A, Yanes O, Agell N, Kozma SC, Gentilella A, Thomas G. Nucleotide depletion reveals the impaired ribosome biogenesis checkpoint as a barrier against DNA damage. EMBO J. 2020 Jul 1;39 (13): e103838. doi: 10.15252/ embj. 2019103838. Epub 2020 Jun 2. PMID: 32484960 Free PMC article.

Tebar F, Chavero A, Agell N, Lu A, Rentero C, Enrich C, Grewal T. Pleiotropic Roles of Calmodulin in the Regulation of KRas and Rac1 GTPases: Functional Diversity in Health and Disease. Int J Mol Sci. 2020 May 23;21 (10): 3680. doi: 10.3390/ ijms21103680. PMID: 32456244 Free PMC article. Review.

Feu, S.; Unzueta, F.; Llopis, A.; Semple, J.; Ercilla, A.; Guaita-Esteruelas, S.; Jaumot, M.; Freire, R.; Agell N. OZF is a Claspin-interacting protein essential to maintain the replication fork progression rate under replication stress. 900388 - The FASEB Journal. 34 - 5, pp. 6907 - 6919. (Estats Units d’Amèrica): The Federation of American Society of Experimental Biology, 2020. ISSN 0892-6638. DOI: https:// doi.org/ 10.1096/ fj.201901926R.

Ercilla, A.; Feu, S.; Aranda, S.; Llopis, A.; Brynjólfsdóttir, S.H.; Sørensen, C.S.; Toledo, L.I.; Agell, N. Acute hydroxyurea-induced replication blockade results in replisome components disengagement from nascent DNA without causing fork collapse. 909449 - Cellular and Molecular Life Sciences. (Suïssa): Springer Verlag, 2019. ISSN 1420-682X. DOI: https: //doi.org/ 10.1007/ s00018-019-03206-1. Handle: http://hdl.handle.net/2445/137967. PMID: 31297568.

Garrido, Eduardo; Jaumot, Montserrat; Agell, Neus; Granadino-Roldan, Jose M.; Rubio-Martinez, Jaime. Toward understanding calmodulin plasticity by molecular dynamics. 915755 - Future Medicinal Chemistry. 11 - 9, pp. 975 -991. (Regne Unit): Future Science, 2019. ISSN 1756-8919. DOI: https: //doi.org/ 10.4155/ fmc-2018-0323. PMID: 31140879.

Garrido E, Lázaro J, Jaumot M, Agell N, Rubio-Martinez J. Modeling and subtleties of K-Ras and Calmodulin interaction. PLoS Comput Biol. 2018 Oct 30; 14(10): e1006552. doi: 10.1371/ journal.pcbi.1006552. PMID: 30376570

Wangsa D, Quintanilla I, Torabi K, Vila-Casadesús M, Ercilla A, Klus G, Yuce Z, Galofré C, Cuatrecasas M, Lozano JJ, Agell N, Cimini D, Castells A, Ried T, Camps J. FASEB J. Near-tetraploid cancer cells show chromosome instability triggered by replication stress and exhibit enhanced invasiveness. 2018 Jul; 32(7): 3502-3517. doi: 10. 1096/ fj.201700247RR. PMID: 29452566

Brun S, Abella N, Berciano MT, Tapia O, Jaumot M, Freire R, Lafarga M, Agell N. SUMO regulates p21Cip1 intracellular distribution and with p21Cip1 facilitates multiprotein complex formation in the nucleolus upon DNA damage. PLoS One. 2017 Jun 5; 12(6): e0178925. doi: 10.1371/ journal.pone.0178925. PMID: 28582471

Ercilla A, Llopis A, Feu S, Aranda S, Ernfors P, Freire R, Agell N. New origin firing is inhibited by APC/CCdh1 activation in S-phase after severe replication stress. Nucleic Acids Res. 2016 Jun 2; 44(10): 4745-62. doi: 10.1093/ nar/ gkw132. Epub 2016 Mar 2. PMID: 26939887

Domínguez D, Feijoo P, Bernal A, Ercilla A, Agell N, Genescà A, Tusell L. Centrosome aberrations in human mammary epithelial cells driven by cooperative interactions between p16INK4a deficiency and telomere-dependent genotoxic stress. Oncotarget. 2015 Sep 29; 6(29): 28238-56. doi: 10.18632/ oncotarget.4958. PMID: 26318587

Barceló C, Etchin J, Mansour MR, Sanda T, Ginesta MM, Sanchez-Arévalo Lobo VJ, Real FX, Capellà G, Estanyol JM, Jaumot M, Look AT, Agell N. Ribonucleoprotein HNRNPA2B1 interacts with and regulates oncogenic KRAS in pancreatic ductal adenocarcinoma cells. Gastroenterology. 2014 Oct; 147(4): 882-892.e8. doi: 10.1053/ j.gastro. 2014.06.041. PMID: 24998203

Barceló C, Paco N, Morell M, Alvarez-Moya B, Bota-Rabassedas N, Jaumot M, Vilardell F, Capella G, Agell N. Phosphorylation at Ser-181 of oncogenic KRAS is required for tumor growth. Cancer Res. 2014 Feb 15; 74(4): 1190-9. doi: 10.1158/ 0008-5472. CAN-13-1750. PMID: 24371225

Barceló C, Paco N, Beckett AJ, Alvarez-Moya B, Garrido E, Gelabert M, Tebar F, Jaumot M, Prior I, Agell N. Oncogenic K-ras segregates at spatially distinct plasma membrane signaling platforms according to its phosphorylation status. J Cell Sci. 2013 Oct 15; 126(Pt 20): 4553-9. doi: 10.1242/ jcs.123737. PMID: 23943869

Llopis A, Salvador N, Ercilla A, Guaita-Esteruelas S, Barrantes Idel B, Gupta J, Gaestel M, Davis RJ, Nebreda AR, Agell N. The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest. Cell Cycle. 2012 Oct 1; 11(19): 3627-37. doi: 10.4161/ cc.21917. PMID: 22935704

Pujols L, Fernández-Bertolín L, Fuentes-Prado M, Alobid I, Roca-Ferrer J, Agell N, Mullol J, Picado C.J. Proteasome inhibition reduces proliferation, collagen expression, and inflammatory cytokine production in nasal mucosa and polyp fibroblasts. Pharmacol Exp Ther. 2012 Oct; 343(1): 184-97. doi: 10.1124/ jpet.111.190710. PMID: 22787116

Ferrándiz N, Caraballo JM, García-Gutierrez L, Devgan V, Rodriguez-Paredes M, Lafita MC, Bretones G, Quintanilla A, Muñoz-Alonso MJ, Blanco R, Reyes JC, Agell N, Delgado MD, Dotto GP, León J. p21 as a transcriptional co-repressor of S-phase and mitotic control genes. PLoS One. 2012; 7(5): e37759. doi: 10.1371/ journal.pone. 0037759. PMID: 22662213

Zanuy M, Ramos-Montoya A, Villacañas O, Canela N, Miranda A, Aguilar E, Agell N, Bachs O, Rubio-Martinez J, Pujol MD, Lee WN, Marin S, Cascante M. Cyclin-dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle. Metabolomics. 2012 Jun 1; 8(3): 454-464. Epub 2011 Jul 8. PMID: 22661920

Alvarez-Moya B, Barceló C, Tebar F, Jaumot M, Agell N. CaM interaction and Ser181 phosphorylation as new K-Ras signaling modulators. Small GTPases. 2011 Mar; 2(2): 99-103.PMID: 21776410

Matito C, Agell N, Sanchez-Tena S, Torres JL, Cascante M. J. Protective effect of structurally diverse grape procyanidin fractions against UV-induced cell damage and death. Agric Food Chem. 2011 May 11; 59(9): 4489-95. doi: 10.1021/ jf103692a. PMID: 21405100

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