at the CNIC

Category: Publications (Page 1 of 6)

Stress-activated kinases signaling pathways in cancer development

Leticia Herrera-Melle, María Crespo, Magdalena Leiva & Guadalupe Sabio.

Cancer is a large group of diseases characterized by abnormal cell growth that can lead to metastasis. It is the second leading cause of death worldwide, and its incidence is expected to rise over the next decades. Stress-activated protein kinases (SAPK) are important players in its regulation. Several studies have tried to unravel their role; however, their pro-tumorigenic or anti-tumorigenic properties are sometimes controversial.

JNK control of tumor microenvironment
JNK control of tumor microenvironment.

In this review, we will discuss the main roles of the different SAPK in the control of tumor development through essential processes such as cell proliferation, apoptosis or invasiveness. We will also show the latest discoveries regarding the contribution of SAPK in shaping tumor microenvironment through the regulation of organ crosstalk and immune cell response during cancer progression.

All these studies are relevant examples of how SAPK offer new therapeutic avenues for cancer patients that may help increase their survival.

Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

Ana Victoria Lechuga-Vieco, Ana Latorre-Pellicer, Iain G. Johnston, Gennaro Prota, Uzi Gileadi, Raquel Justo-Méndez, Rebeca Acín-Pérez, Raquel Martínez-de-Mena, Jose María Fernández-Toro, Daniel Jimenez-Blasco, Alfonso Mora, Jose A. Nicolás-Ávila, Demetrio J. Santiago, Silvia G. Priori, Juan Pedro Bolaños, Guadalupe Sabio, Luis Miguel Criado, Jesús Ruíz-Cabello, Vincenzo Cerundolo, Nick S. Jones, José Antonio Enríquez.

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development.

Mitochondria (Image: Alfonso Mora).

Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases.

Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type–specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.

JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma

Elisa Manieri, Cintia Folgueira, María Elena Rodríguez, Luis Leiva-Vega, Laura Esteban-Lafuente, Chaobo Chen, Francisco Javier Cubero, Tamera Barrett, Julie Cavanagh-Kyros, Davide Seruggia, Alejandro Rosell, Fátima Sanchez-Cabo, Manuel Jose Gómez, Maria J. Monte, Jose J. G. Marin, Roger J. Davis, Alfonso Mora & Guadalupe Sabio.

Obesity is associated with hepatic steatosis and activation of the cJun NH2-terminal kinase (JNK) stress-signaling pathway. Studies in mice demonstrate that JNK deficiency in the liver prevents the development of hepatic steatosis. This observation suggests that inhibition of JNK signaling may represent a possible treatment for hepatic steatosis. However, the long-term consequences of JNK inhibition are poorly understood.

Liver cholangiocarcinoma (Photo: Chaobo Chen).

Here we demonstrate that loss of JNK causes changes in cholesterol and bile acid metabolism that promote cholestasis, bile duct proliferation, and intrahepatic cholangiocarcinoma. We identify PPARα activation as the molecular mechanism that accounts for this phenotype .

Our analysis has important implications for the long-term use of JNK inhibitors for the treatment of obesity.

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