Current Molecular Medicine (v.13, #2)

Editorial (Hot Topic: Signaling in Cell Death, Survival, Proliferation and Degeneration) by S. S. Smaili, A. F.G. Quest, C. Hetz, Sergio Lavandero (239-240).

Autophagy and Toxins: A Matter of Life or Death by M. B. Mestre, M. I. Colombo (241-251).
Bacterial protein toxins are important virulence factors. A particular class of toxins, the pore-form toxins (PFTs), shares the toxigenic mechanism of forming pores in the membrane of target cells. The relationship between autophagy and bacterial PFTs has been described for several toxin-secreting pathogens and in this review we have recapitulated the more recent findings on this issue. A common outcome is that the target cell, by a yet non-completely defined mechanism, senses the toxin attack and builds up complex responses as a protective mechanism for host survival. However, in some cases, this cellular response is beneficial to the microorganism by supplying an intracellular niche or by promoting host-cell death, which facilitates pathogen spreading.

The Role of Calcium Stores in Apoptosis and Autophagy by S. S. Smaili, G. J.S. Pereira, M. M. Costa, K. K. Rocha, L. Rodrigues, L. G. do Carmo, H. Hirata, Y.-T. Hsu (252-265).
The mechanisms that regulate programmed cell death, such as apoptosis, and the cellular “selfeating” phenomenon of autophagy, share many regulatory systems and common pathways. These mechanisms have been extensively investigated over the last few years. Some intracellular structures may determine and control the autophagic fate of the cell such as the endoplasmic reticulum, mitochondria, and lysosomes. The coordination and interrelation of these organelles are crucial in maintaining calcium levels and general cellular homeostasis, as well as in regulating cell life and death under physiological and pathological conditions, including cancer, neurodegeneration, and aging. In this review, we discuss the crosstalk between the aforementioned organelles and their influence in apoptotic and autophagic processes.

The Caveolin-1 Connection to Cell Death and Survival by A. F.G. Quest, L. Lobos-Gonzalez, S. Nunez, C. Sanhueza, J.-G. Fernandez, A. Aguirre, D. Rodriguez, L. Leyton, V. Torres (266-281).
Caveolins are a family of membrane proteins required for the formation of small plasma membrane invaginations called caveolae that are implicated in cellular trafficking processes. In addition to this structural role, these scaffolding proteins modulate numerous intracellular signaling pathways; often via direct interaction with specific binding partners. Caveolin-1 is particularly well-studied in this respect and has been attributed a large variety of functions. Thus, Caveolin-1 also represents the best-characterized isoform of this family with respect to its participation in cancer. Rather strikingly, available evidence indicates that Caveolin-1 belongs to a select group of proteins that function, depending on the cellular settings, both as tumor suppressor and promoter of cellular traits commonly associated with enhanced malignant behavior, such as metastasis and multi-drug resistance. The mechanisms underlying such ambiguity in Caveolin-1 function constitute an area of great interest. Here, we will focus on discussing how Caveolin-1 modulates cell death and survival pathways and how this may contribute to a better understanding of the ambiguous role this protein plays in cancer.

The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions by A. Diez-Fraile, T. Lammens, Y. Benoit, K. G.M.A. D'Herde (282-295).
The calcium-sensing receptor (CaSR) belongs to the evolutionarily conserved family of plasma membrane G protein-coupled receptors (GPCRs). Early studies identified an essential role for the CaSR in systemic calcium homeostasis through its ability to sense small changes in circulating calcium concentration and to couple this information to intracellular signaling pathways that influence parathyroid hormone secretion. However, the presence of CaSR protein in tissues is not directly involved in regulating mineral ion homeostasis points to a role for the CaSR in other cellular functions including the control of cellular proliferation, differentiation and apoptosis. This position at the crossroads of cellular fate designates the CaSR as an interesting study subject is likely to be involved in a variety of previously unconsidered human pathologies, including cancer, atherosclerosis and Alzheimer's disease. Here, we will review the recent discoveries regarding the relevance of CaSR signaling in development and disease. Furthermore, we will discuss the rational for developing and using CaSR-based therapeutics.

PRAME/EZH2-Mediated Regulation of TRAIL: A New Target for Cancer Therapy by D. D. De Carvalho, B. P. Mello, W. O. Pereira, G. P. Amarante-Mendes (296-304).
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exerts a cancer cell-specific pro-apoptotic activity. This property made the TRAIL associated pathway one of the most promising strategies aimed at inducing tumor-selective death. In fact, several approaches have been considered to explore this pathway for cancer therapy, such as recombinant TRAIL, agonist antibodies for TRAIL receptors, and adenoviral TRAIL. However, all of these approaches have certain disadvantages that limit their clinical use. Our recent discovery that the complex PRAME/EZH2 is able to repress TRAIL expression, in a cancer-specific manner, suggests an alternative approach for combined cancer therapy. A genetic or pharmacological inhibition of TRAIL repressors in cancer cells could restore endogenous TRAIL expression, thereby overcoming some of the limitations of and/or cooperating with previous approaches.

A179L, a New Viral Bcl2 Homolog Targeting Beclin 1 Autophagy Related Protein by B. Hernaez, M. Cabezas, R. Munoz-Moreno, I. Galindo, M. A. Cuesta-Geijo, C. Alonso (305-316).
Autophagy is a relevant cellular defense mechanism that directly eliminates intracellular pathogens and has a crucial role for innate and adaptive immune responses. Some viruses have developed tools to counteract this cellular response. A179L, the viral Bcl2 homolog of African swine fever virus, interacts with proapoptotic Bcl2 family proteins to inhibit apoptosis. Here we report that this gene manipulates autophagy by interacting with Beclin 1 through its BH3 homology domain. At subcellular level, A179L colocalized with Beclin 1 at mitochondria and the endoplasmic reticulum. Virus infection inhibited autophagosome formation in cells; however, when autophagy was induced prior to or at the time of infection the number of infected cells was severely decreased.

Cell Death and Survival Through the Endoplasmic Reticulum- Mitochondrial Axis by R. Bravo-Sagua, A. E. Rodriguez, J. Kuzmicic, T. Gutierrez, C. Lopez-Crisosto, C. Quiroga, J. Diaz-Elizondo, M. Chiong, T. G. Gillette, B. A. Rothermel, S. Lavandero (317-329).
The endoplasmic reticulum has a central role in biosynthesis of a variety of proteins and lipids. Mitochondria generate ATP, synthesize and process numerous metabolites, and are key regulators of cell death. The architectures of endoplasmic reticulum and mitochondria change continually via the process of membrane fusion, fission, elongation, degradation, and renewal. These structural changes correlate with important changes in organellar function. Both organelles are capable of moving along the cytoskeleton, thus changing their cellular distribution. Numerous studies have demonstrated coordination and communication between mitochondria and endoplasmic reticulum. A focal point for these interactions is a zone of close contact between them known as the mitochondrial-associated endoplasmic reticulum membrane (MAM), which serves as a signaling juncture that facilitates calcium and lipid transfer between organelles. Here we review the emerging data on how communication between endoplasmic reticulum and mitochondria can modulate organelle function and determine cellular fate.