Molecular mechanisms of hepatitis C virus–induced hepatocellular carcinoma

n/

Autophagy in major human diseases

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders

Inhibition of in vitro muscle differentiation by the immortalizing oncogene Py LT-Ag

The interference of Polyomavirus (Py) early functions with in vitro myogenic differentiation is the object of this study. Single cell analysis of C2 myogenic Py infected cells showed a mutual exclusion between Py early functions and muscle gene expression. The morphological and biochemical analysis of clones obtained from C2 cells stably transfected with a plasmid carrying an ORI- Py genome, showed that myogenesis is blocked and cells display the transformed phenotype. By using plasmids separately encoding Middle T or Large T functions, the involvement of individual early viral gene products was determined. Py Middle T alone does not inhibit myotube formation even though cells are morphologically transformed. Myogenic differentiation, on the other hand, is inhibited by Py Large T. This inhibition, which is proportional to the level of Py Large T expression, does not entail to require alteration of cell growth properties and acts by blocking the expression of myogenin and terminal differentiation markers without altering the expression of the regulatory gene MyoD

Inhibition of in vitro myogenic differentiation by a polyomavirus early function

In the present work we report on the role of a polyomavirus (Py) early function in interfering with both morphological and biochemical differentiation of the myogenic C2 cell line. The analysis of cell clones stably transfected with a plasmid carrying an ORI- Py genome showed that in the presence of the whole viral early region myogenesis is blocked and a transformed phenotype is evident. By using a plasmid that only encodes large-T function, the involvement of this individual early viral gene product was determined. Inhibition of myogenic differentiation by Py large T is proportional to the level of its expression. This inhibition does not appear to require alteration of cell growth properties. The analysis of muscle-specific functions expressed at different steps in the myogenic pathway showed that Py large T blocks the expression of terminal differentiation markers without altering the expression of the regulatory gene MyoD

Why is autophagy important for melanoma? Molecular mechanisms and therapeutic implications.

As the principle lysosomal mediated mechanism for the degradation of aged or damaged organelles and proteins, autophagy (self-eating) is generally considered a pro-survival process activated by cells to sustain life in presence of adverse environmental conditions such as nutrient shortage and/or in presence of cytotoxic compounds [1]. Upon activation, cytoplasmic material is sequestered into double-membrane vesicles (autophagosomes) then targeted for degradation by fusion with lysosomes (autolysosomes); metabolic activity and cell survival are consequently sustained by recycling the degradation products. Basal autophagy occurs in almost all cell types, though at different degree, as a finely regulated "quality control" process to prevent cell damage, for the demolition of cellular structures during cell/tissue remodelling, and to ensure the maintenance of cellular homeostasis through recycling cellular components/molecules [2,3]. Autophagy is stimulated in response to both physiological and pathological conditions such as starvation, hypoxia and low energy, pathogen infection and protein aggregates. Although it's clear that autophagy is also involved in cancer, its role, however, is complex since it can both suppress and promote tumorigenesis [4]. Consequently, it is generally accepted that while autophagy is used by advanced stage cancers to maintain tumour survival, loss of autophagy in earlier stages is associated with tumour development. Accordingly, it is now apparent that aberrant control of autophagy is among key hallmarks of cancer, with several studies now demonstrating this process is deregulated also in melanoma [5,6]

Autophagy in development and regeneration: role in tissue remodelling and cell survival

Morphogenetic events that occur during development and regeneration are energy demanding processes requiring profound rearrangements in cell architecture, which need to be coordinated in timely fashion with other cellular activities, such as proliferation, migration and differentiation. In the last 15 years, it has become evident that autophagy, an evolutionarily-conserved catabolic process that mediates the lysosomal turnover of organelles and macromolecules, is an essential " tool" to ensure remodelling events that occur at cellular and tissue levels. Indeed, studies in several model organisms have shown that the inactivation of autophagy genes has a significant impact on embryogenesis and tissue regeneration, leading to extensive cell death and persistence of unnecessary cell components. Interestingly, the increased understanding of the mechanisms that confers selectivity to the autophagic process has also contributed to identifying development-specific targets of autophagy across species. Moreover, alternative ways to deliver materials to the lysosome, such as microautophagy, are also emerging as key actors in these contexts, providing a more complete view of how the cell component repertoire is renovated. In this review, we discuss the role of different types of autophagy in development and regeneration of invertebrates and vertebrates, focusing in particular on its contribution in cnidarians, platyhelminthes, nematodes, insects, zebrafish and mammals

Tissue transglutaminase contributes to the formation of disulphide bridges in proteins of mitochondrial respiratory complexes

In this study we provide the first in vivo evidences showing that, under physiological conditions, "tissue" transglutaminase (TG2) might acts as a protein disulphide isomerase (PDI) and through this activity contributes to the correct assembly of the respiratory chain complexes. Mice lacking TG2 exhibit mitochondrial energy production impairment, evidenced by decreased ATP levels after physical challenge. This defect is phenotypically reflected in a dramatic decrease of motor behaviour of the animals. We propose that the molecular mechanism, underlying such a phenotype.. resides in a defective disulphide bonds formation in ATP synthase (complex V), NADH-ubiquinone oxidoreductase (complex I), succinate-ubiquinone oxidoreductase (complex II) and cytochrome c oxidase (complex IV). In addition, TG2-PDI might control the respiratory chain by modulating the formation of the prohibitin complexes. These data elucidate a new pathway that directly links the TG2-PDI enzymatic activity with the regulation of mitochondrial respiratory chain function. (c) 2006 Elsevier B.V. All rights reserved

Autophagy in major human diseases

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders