Molecular targets in health and disease: focus on PI3-kinase

ACCarrera

 

Ana C. Carrera

Group Leader

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Research summary

Two biological problems have occupied the activity of our team (~12 to 15 members): cancer and inflammation. Our recent work is based in the assumption that the same biological activities that control physiological responses also control pathology when deregulated. The team is currently working on class I phosphoinositide 3-kinase (PI3K), with special emphasis on examining the specific function of each of the four class I PI3K isoforms in physiology and disease.

 

Publications

Vallejo-Díaz J, Olazabal-Morán M, Cariaga-Martínez AE, Pajares MJ, Flores JM, Pio R, Montuenga LM, Carrera AC. Targeted depletion of PIK3R2 induces regression of lung squamous cell carcinoma. Oncotarget 2016; 7:85063-78

Millán-Uclés Á, Zuluaga S, Marqués M, Vallejo-Díaz J, Sanz L, Cariaga-Martínez AE, Real FX, Carrera AC.  E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing. Oncotarget 2016; 7:84054-71

Redondo-Muñoz J, Pérez-García V, Rodríguez MJ, Valpuesta JM, Carrera AC. Phosphoinositide 3-kinase beta protects nuclear envelope Integrity by controlling RCC1 localization and Ran activity. Mol Cell Biol 2015; 35:249-63

Redondo-Muñoz J, Pérez-García V, Carrera AC. Phosphoinositide 3-kinase beta: when a kinase is more than a kinase. Trends Cell Mol Biol 2014; 8:83-92

Suárez-Fueyo A, Rojas JM, Cariaga AE, García E, Steiner BH, Puri KD, Barber DF, Carrera AC. Inhibition of PI3Kδ reduces kidney infiltration by macrophages and ameliorates systemic lupus in the mouse. J Immunol 2014; 193:544-554

 

decreased invadopodia in p85b def cellsWe focus on the molecular mechanisms by which kinases control cell behaviour and, when altered, human disease. In recent years, we have concentrated especially on phosphoinositide 3-kinases (PI3-kinases), an enzyme that generates the PIP3 product, which is increased in cancer and autoimmunity as it triggers cell survival, invasion and division.

PI3-kinase mouse models and biochemical approach.

PI3-kinases are heterodimers composed of a p110-catalytic and a p85-regulatory subunit. p110alpha and beta, and associated p85alpha and p85beta, are ubiquitous and are altered in cancer, whereas p110delta and the closely-related p110gamma isoform are more abundant in hematopoietic cells; when deregulated, they are involved in development of chronic inflammation/autoimmunity. In animal models, we study the physiological function of PI3K and the consequences of its deregulation in cancer and autoimmunity.

Mechanism of PI3-kinase beta action on DNA/chromatin remodelling.

The PI3-kinase pathway is frequently altered in cancer. Many laboratories and companies have focused on PI3-kinase alpha; we study the less well-known PI3-kinase beta isoform. We showed that PI3-kinase beta (p110beta) localizes to the nucleus and regulates DNA replication, segregation and repair. We aim to determine the molecular basis of p110beta action on DNA homeostasis and chromatin remodelling in cancer and stem cells to understand why certain tumour types increase p110beta expression.

Alternative cancer treatment based in interfering molecules.

Metastasis remains the leading cause of death from many tumours. The PIP3 product enables cell survival; for this reason, cells with altered regulation of PI3-kinase alpha or beta, or with mutations in the phosphatase PTEN (which reduces PIP3 levels), are present in ~50% of human tumours, most often at metastatic phases.

PI3-kinase is a key target in cancer, but only broad-spectrum inhibitors or p110alpha inhibitors are being tested clinically. Our aim is to develop a strategy for the treatment of tumours accessible by endoscopy (or orally), based on delivery of interfering molecules (RNA and peptides). The first target selected is p85beta. p85 subunits regulate the activity and localisation of this enzyme. Normal cells express mainly p85alpha, while some tumour types show predominant p85beta expression that correlates with metastasis. In parallel to defining p85beta mechanism of action in metastasis, we study the effect of interfering with p85beta action in an established tumour in the mouse.

 

defects in nucleocytoplasmic traffic in PIK3CB def cells

 grupoCarreraRed 

Name
Position
Contact
Ana Clara Carrera Principal investigator
Ana María González-García Postdoctoral scientist
Rosa Varona Valle Postdoctoral scientist
África Millán Ucles Postdoctoral scientist
Jesús Vallejo Díaz Predoctoral scientist
Carmen Hernández Agüero Technician
Lorena Sanz González Technician

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