How does full repression of cell cycle gene occur during differentiation ?

The ability of the retinoblastoma protein (pRB) to restrict the cell cycle is well known. Since KDM5A/RBP2/JARID1A is associated with pRB/E2F, one may wonder about its recruitment and its role in the cell cycle. In our study we determined how KDM5A uses its demethylating capability on cell cycle genes during differentiation. We also wanted to know if the demethylation function of KDM5A is non-redundant. It was previously shown that KDM5A and E2F colocalize. We aimed to know at what point of the cell cycle KDM5A is recruited, and whether E2F plays a role in KDM5A recruitment or vice-versa. We focused on the genomic localization of KDM5A in mouse ES cells and human U937 cells at different stages of development.

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Insights into 14-3-3σ-mediated NF-κB role in breast cancer

14-3-3σ is an adaptor protein that regulates multiple signal transduction pathways. It has been described as a tumour suppressor in breast cancer, where it is often lost or repressed. Anna Bigas and Lluís Espinosa lab, from IMIM, had reported before that 14-3-3 proteins facilitated the nuclear export of p65 and were essential to regulate NF-κB signalling, after stimulation by TNFα.

Last week a paper came out where the role of 14-3-3σ in cancer relapse and metastasis is further investigated, and the kinetics of nuclear p65 export after TNFα stimulation are described. This work has been led by  Anna Bigas and Lluís Espinosa and is the result of a collaboration between reserach groups from the IRB the Hospital del Mar and our group at the UPF. In this publication we contributed in the microarray data interpretation, to describe a genetic signature that responds to TNFα in a 14-3-3σ-dependent manner in MCF7 breast cancer cells. Its over-expression moreover correlates with poor relapse-free survival breast cancer patients. We used IntOGen and Gitools to determine that those genes are associated to breast, intestinal, ovarian and lung cancer. These findings identify a genetic signature that is moreover important for breast cancer prognosis and for future personalized treatments based on NF-κB targeting.

It is always exciting  to blend computational biology analyses and molecular genetics experiments to build a solid story such as this one. I am very glad we had the chance to contribute to it with our knowledge, since I could learn thanks to that.

 

Inglés-Esteve J, Morales M, Dalmases A, Garcia-Carbonell R, Jené-Sanz A, Lopez-Bigas N, Iglesias M, Ruiz-Herguido C, Rovira A, Rojo F, Albanell J, Gomis RR, Bigas A, Espinosa L. Inhibition of specific NF-kappaB activity contributes to the tumor suppressor function of 14-3-3sigma in breast cancer. PLoS ONE, 7(5): e38347. doi:10.1371/journal.pone.0038347

 

p27 (Kip1) role as a transcriptional regulator

p27, also called Kip1, is a well known protein with a crucial role in cell cycle progression and cancer. p27 best known function is the inhibition of cyclin-dependent kinase (cdk) activities, cyclin E-CDK2 and cyclin D-CDK4 complexes, and has a role in controlling the cell cycle progression at G1. However it was unclear if p27 may have other roles in the nucleus other than acting as a CDK inhibitor.

paper published this week in Oncogene shows that p27 has also a role as a transcriptional repressor, which is independent of cyclin-cdk regulation. This work has been leaded by Oriol Bachs and Raffy Pippa from IDIBAPS, and we, Gunes and myself, and other researchers from IMIMCIEMAT and University of Toulouse have participated in the project.

Model illustrating the participation of p27 on the organization of p130/E2F4 repressor complexes. p130 first drives E2F4 to the promoters, then p27 is subsequently loaded by directly interacting by its carboxyl-domain with both p130 and E2F4. Finally, p27 recruits the co-repressors HDAC1 and mSIN3A on these promoters.

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Histone-modifying Enzymes Coregulated in Cancer – a phenomena that can be used for better drug design

4 of the 5 participants in the project, from left to right: Liza, Laura, William and Khademul

Recently epigenetic modifications have drawn lots of attention in the oncology field. Cancer is characterized by aberrant patterns of gene expression of multiple genes. These major shifts in gene expression are believed to be due to genetic and epigenetic changes. Read the rest of this entry »

SVGMap: Configurable image browser for experimental data

Have you ever heard of SVG? Scalable Vector Graphics (SVG) is an open standard to design images and graphics that can be scaled to any size without loosing quality. SVG is also the focus of a tool that we have developed in our group to cover specific needs of a collaborative project with an experimental group. The need was to visualize the spatial distribution of the expression of selected genes in different tissues and cell types. Read the rest of this entry »