A. Rimessi | University of Ferrara (original) (raw)
Papers by A. Rimessi
Oncogene, 2019
Metformin is a hypoglycaemic agent used to treat type 2 diabetes mellitus (DM2) patients, with a ... more Metformin is a hypoglycaemic agent used to treat type 2 diabetes mellitus (DM2) patients, with a broad safety profile. Since previous epidemiological studies had shown that the incidence of hepatocellular carcinoma (HCC) decreased significantly in metformin treated DM2 patients, we hypothesised that intervention with metformin could reduce the risk of neoplastic transformation of hepatocytes. HCC is the most common primary liver malignancy and it generally originates in a background of liver fibrosis and cirrhosis. In the present study, we took advantage of a transgenic mouse (TG221) characterized by microRNA-221 overexpression, with cirrhotic liver background induced by chronic administration of carbon tetrachloride (CCl4). This mouse model develops fibrosis, cirrhosis and liver tumours that become visible in 100% of mice at 5-6 months of age. Our results demonstrated that metformin intervention improves liver function, inhibits hepatic stellate cell (HSC) activation, reduces liver fibrosis, depletes lipid accumulation in hepatocytes, halts progression to decompensated cirrhosis and abrogates development HCC in CCl4 challenged transgenic mouse model. The study establishes the rationale for investigating metformin in cirrhotic patients regardless of concomitant DM2 status. 28 background of chronic liver disease and cirrhosis, which 29 represents the most important risk factor for HCC [2]. Q4 The 30 extended time of progression from liver fibrosis to malig-31 nancy make individuals at risk for HCC identifiable and 32 candidates for chemoprevention strategies to delay or stop 33 the natural course of chronic liver disease and curtail HCC 34 incidence and mortality [3]. Q5 35 Hepatitis B vaccination programs or anti-hepatitis C 36 therapeutics are examples of approaches that not only pro-37 tect from viral infection, but also reduce the incidence of 38 virus-associated HCC [4, 5]. However, non-viral causes 39 namely alcoholic or non-alcoholic fatty liver disease 40 (NAFLD) and non-alcoholic steatohepatitis Q6 (NASH) 41 account for nearly 46% liver cancer deaths [6]. Addition-42 ally, increasing epidemic of obesity and type 2 diabetes 43 mellitus (DM2), both important risk factors of NAFLD and 44 NASH, might emerge as dominant risk factors for HCC 45 incidence in future [7, 8]. Hence, prevention programs can 46 have an important impact in decreasing HCC occurrence. 47 Metformin is a first-line dimethylbiguanide hypogly-48 caemic agent used to treat DM2 patients, with a broad safety 49 profile. Abundant epidemiological data have indicated that 50 incidence of several cancers, including HCC decreased
European Psychiatry
Antipsychotic drugs are currently used in clinical practice for a variety of mental disorders. Cl... more Antipsychotic drugs are currently used in clinical practice for a variety of mental disorders. Clozapine is the most effective medication for treatment-resistant schizophrenia, in controlling aggression and suicidal behavior in psychosis. Although clozapine is associated with a low likelihood of extrapyramidal symptoms and other neurological side effects, weight gain and metabolic side effects are well known in clinical practice exposing the patient to a greater risk of cardiovascular disorders, premature death, as well as psychosocial issues leading to non-adherence. The mechanisms underlying this pharmacologically activated disorders are still controversial. Based on our in vitro results, we have characterized in vivo the effects of the selective PKCβ inhibitor, Ruboxistaurin (LY-333531) on a preclinical model of long-term clozapine-induced weight gain. Cell biology, biochemistry and psychomotor tests have been performed on wild type and PKCβ (-/-) mutant mice to investigate the c...
Drugs that target human thymidylate synthase (hTS) are widely used in anti-cancer therapy. Howeve... more Drugs that target human thymidylate synthase (hTS) are widely used in anti-cancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces its over-expression and the development of drug resistance. We thus pursued an alternative strategy that led to the discovery of TS-dimer disrupters that bind at the monomer-monomer interface and shift the dimerization equilibrium of both the recombinant and the intracellular protein toward the inactive monomers. We performed a structural, spectroscopic and kinetic investigation of the effects of these small molecules andthe best one, E7, accelerates the proteasomal degradation of hTS in cancer cells. E7 showed a superior anticancer profile to fluorouracil in a mouse model of human pancreatic and ovarian cancer. Thus, over sixty years after the discovery of the first TS prodrug inhibitor, fluorouracil, E7 breaks the link between TS inhibition and enhanced expression in response, providing a strategy to fight drug-r...
Chirurgia italiana
The preservation of livers to be transplanted is currently obtained by static cold storage at 4 C... more The preservation of livers to be transplanted is currently obtained by static cold storage at 4 C degrees and flushing with UW solution. New methods of preservation are being studied that take advantage of machines for continuous hypothermic perfusion of the organ. Such machines have permitted a lengthening of preservation times and the use of livers from non-beating-heart donors. In an attempt to eliminate the damage due to hypothermia, to lengthen preservation times, and to extend the availability of livers to be transplanted, also using those subjected to short periods of warm ischaemia, we have constructed a transportable machine that produces a hyperbaric atmosphere and allows continuous perfusion of the liver. Ten pig livers from beating-heart donors were perfused with Ringer solution in hyperbaric conditions with oxygen at temperatures ranging from 10 to 25 degrees C for periods of up to 24 hours and studied by means of histopathological analysis and tests of mitochondrial ac...
Annals of the New York Academy of Sciences, 2007
In mammals, four different genes encode four PMCA isoforms. PMCA1 and PMCA4 are expressed ubiquit... more In mammals, four different genes encode four PMCA isoforms. PMCA1 and PMCA4 are expressed ubiquitously. PMCA2 and PMCA3 are expressed prevalently in the central nervous systems. More than 30 variants are generated by mechanisms of alternative splicing. The physiological meaning of the existence of such elevated number of isoforms is not clear, but it would be plausible to relate it to the cell-specific demands of Ca 2+ homeostasis. To characterize functional specificity of PMCA variants we have investigated two aspects: the effects of the overexpression of the different PMCA variants on cellular Ca 2+ handling and the existence of possible isoform-specific interactions with partner proteins using a yeast two-hybrid technique. The four basic PMCA isoforms were coexpressed in CHO cells together with the Ca 2+ -sensitive recombinant photoprotein aequorin. The effects of their overexpression on Ca 2+ homeostasis were monitored in the living cells. They had revealed that the ubiquitous isoforms 1 and 4 are less effective in reducing the Ca 2+ peaks generated by cell stimulation as compared to the neuronspecific isoforms 2 and 3. To establish whether these differences were related to different and new physiological regulators of the pump, the 90 N-terminal residues of PMCA2 and PMCA4 have been used as baits for the search of molecular partners. Screening of a human brain cDNA library with the PMCA4 bait specified the -isoform of protein 14-3-3, whereas no 14-3-3 clone was obtained with the PMCA2 bait. Overexpression of PMCA4/14-3-3 (but not of PMCA2/14-3-3 ) in HeLa cells together with targeted aequorins showed that the ability of the cells to export Ca 2+ was impaired. Thus, the interaction with 14-3-3 inhibited PMCA4 but not PMCA2. The role of PMCA2 has been further characterized by Ca 2+ measurements in cells overexpressing different splicing variants. The results indicated that the combination of alternative
EMBO molecular medicine, Jan 28, 2015
Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately ... more Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately 0.3-0.5% of the population and is characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhages. Cerebral cavernous malformation is a genetic disease that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Causative loss-of-function mutations have been identified in three genes, KRIT1 (CCM1), CCM2 (MGC4607), and PDCD10 (CCM3), which occur in both sporadic and familial forms. Autophagy is a bulk degradation process that maintains intracellular homeostasis and that plays essential quality control functions within the cell. Indeed, several studies have identified the association between dysregulated autophagy and different human diseases. Here, we show that the ablation of the KRIT1 gene strongly suppresses autophagy, leading to the abe...
Cell death & disease, 2012
Ca²⁺ transfer from endoplasmic reticulum (ER) to mitochondria can trigger apoptotic pathways by i... more Ca²⁺ transfer from endoplasmic reticulum (ER) to mitochondria can trigger apoptotic pathways by inducing release of mitochondrial pro-apoptotic factors. Three different types of inositol 1,4,5-trisphosphate receptor (IP₃R) serve to discharge Ca²⁺ from ER, but possess some peculiarities, especially in apoptosis induction. The anti-apoptotic protein Akt can phosphorylate all IP₃R isoforms and protect cells from apoptosis, reducing ER Ca²⁺ release. However, it has not been elucidated which IP₃R subtypes mediate these effects. Here, we show that Akt activation in COS7 cells, which lack of IP₃R I, strongly suppresses IP₃-mediated Ca²⁺ release and apoptosis. Conversely, in SH-SY 5Y cells, which are type III-deficient, Akt is unable to modulate ER Ca²⁺ flux, losing its anti-apoptotic activity. In SH-SY 5Y-expressing subtype III, Akt recovers its protective function on cell death, by reduction of Ca²⁺ release. Moreover, regulating Ca²⁺ flux to mitochondria, Akt maintains the mitochondrial i...
Frontiers in Oncology, 2013
Atypical protein kinase C isoforms are serine threonine kinases involved in various pathological ... more Atypical protein kinase C isoforms are serine threonine kinases involved in various pathological conditions. In recent years, the PKCζ isoform has emerged as an important regulator of multiple cellular processes operating in cancer. In this review, we will focus on the PKCζ isoform as an oxidative-sensing kinase involved in cancer-related inflammation and chemoresistance. We will discuss its nuclear localization and its possible pivotal role in connecting inflammation with drug resistance.
Novartis Foundation Symposia, 2007
PA-GFP: a window into the subcellular adventures of the individual mitochondrion 21 Discussion 36... more PA-GFP: a window into the subcellular adventures of the individual mitochondrion 21 Discussion 36 Luca Scorrano Multiple functions of mitochondria-shaping proteins 47 Discussion 55 Bruce M. Spiegelman Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators 60
Methods in Cell Biology, 2007
Science, 2007
human tracheal epithelial cells expressing high amounts of terminal a2,6 SA motifs and, simultane... more human tracheal epithelial cells expressing high amounts of terminal a2,6 SA motifs and, simultaneously, in an improved ability to overcome the inhibitory effects of human bronchial mucins associated with a2,3 SA receptors (28). However, mutations that caused a shift from the avian-type to human-type receptor binding specificity for the H1 subtype do not cause an equivalent shift in specificity for the H5 subtype (24). Likewise, the amino acid changes required to alter the H3 HA from an avian-to human-type receptor binding specificity are different from those required for the H1 HA. Therefore, it is likely that different avian HA subtypes have different structural requirements to confer receptor specificity. Thus, it is currently unknown which additional mutations in the H5 HAwould cause a shift to the human-type specificity, which may be required for H5N1 viruses to transmit efficiently among humans.
Purinergic Signalling, 2012
Since 1929, when it was discovered that ATP is a substrate for muscle contraction, the knowledge ... more Since 1929, when it was discovered that ATP is a substrate for muscle contraction, the knowledge about this purine nucleotide has been greatly expanded. Many aspects of cell metabolism revolve around ATP production and consumption. It is important to understand the concepts of glucose and oxygen consumption in aerobic and anaerobic life and to link bioenergetics with the vast amount of reactions occurring within cells. ATP is universally seen as the energy exchange factor that connects anabolism and catabolism but also fuels processes such as motile contraction, phosphorylations, and active transport. It is also a signalling molecule in the purinergic signalling mechanisms. In this review, we will discuss all the main mechanisms of ATP production linked to ADP phosphorylation as well the regulation of these mechanisms during stress conditions and in connection with calcium signalling events. Recent advances regarding ATP storage and its special significance for purinergic signalling will also be reviewed.
Proceedings of the National Academy of Sciences, 2008
Regeneration of mesenchymal tissues depends on a resident stem cell population, that in most case... more Regeneration of mesenchymal tissues depends on a resident stem cell population, that in most cases remains elusive in terms of cellular identity and differentiation signals. We here show that primary cell cultures derived from adipose tissue or skeletal muscle differentiate into adipocytes when cultured in high glucose. High glucose induces ROS production and PKC activation. These two events appear crucial steps in this differentiation process that can be directly induced by oxidizing agents and inhibited by PKC siRNA silencing. The differentiated adipocytes, when implanted in vivo, form viable and vascularized adipose tissue. Overall, the data highlight a previously uncharacterized differentiation route triggered by high glucose that drives not only resident stem cells of the adipose tissue but also uncommitted precursors present in muscle cells to form adipose depots. This process may represent a feed-forward cycle between the regional increase in adiposity and insulin resistance that plays a key role in the pathogenesis of diabetes mellitus.
Proceedings of the National Academy of Sciences, 2009
Despite the growing interest in the Fhit tumor suppressor protein, frequently deleted in human ca... more Despite the growing interest in the Fhit tumor suppressor protein, frequently deleted in human cancers, the mechanism of its powerful proapoptotic activity has remained elusive. We here demonstrate that Fhit sensitizes the low-affinity Ca(2+) transporters of mitochondria, enhancing Ca(2+) uptake into the organelle both in intact and in permabilized cells, and potentiating the effect of apoptotic agents. This effect can be attributed to the fraction of Fhit sorted to mitochondria, as a fully mitochondrial Fhit (a chimeric protein including a mitochondrial targeting sequence) retains the Ca(2+) signaling properties of Fhit and the proapoptotic activity of the native protein (whereas the effects on the cell cycle are lost). Thus, the partial sorting of Fhit to mitochondria allows to finely tune the sensitivity of the organelle to the highly pleiomorphic Ca(2+) signals, synergizing with apoptotic challenges. This concept, and the identification of the molecular machinery, may provide ways to act on apoptotic cell death and its derangement in cancer.
The Pharmacogenomics Journal, 2010
Atypical antipsychotics (APDs) are currently used in clinical practice for a variety of mental di... more Atypical antipsychotics (APDs) are currently used in clinical practice for a variety of mental disorders such as schizophrenia, bipolar disorder and severe behavioral disturbances. A well-known disadvantage of using these compounds is a propensity for weight gain, resulting frequently in obesity. The mechanisms underlying pharmacologically induced weight gain are still controversial. The objective of this study was to evaluate in vitro the effects of different APDs on adipogenic events in cultured human pre-adipocytes and in rat muscle-derived stem cells (MDSCs), aiming to identify a common intracellular event contributable to these drugs. Culture behavior was evaluated in terms of cell proliferation, lipid accumulation, gene expression and morphological features. Results indicate that APDs influence adipogenic events through changes in the differentiation and proliferation of preadipocytes and MDSCs that are brought on by protein kinase C-b (PKC-b) activation. These data identify a signaling route that could be a potential target of pharmacological approaches for preventing the weight gain associated with APD treatment.
Oncogene, 2014
A growing body of research has highlighted the complex range of tumoral traits acquired during H-... more A growing body of research has highlighted the complex range of tumoral traits acquired during H-Ras-driven transformation and maintenance, which include proliferative signaling, growth suppressor evasion and resistance to cell death. Clear molecular information about these processes is not yet available, but recent evidence has provided solid support for the importance of mitochondria. Here, we show that the induction of oncogenic H-Ras leads to changes in intracellular calcium (Ca 2 þ ), evaluate the temporal relationship between oncogene expression and mitochondrial physiology, and demonstrate that Ca 2 þ homeostasis is altered by caveolin-1, a protein that has a key role in tumor maintenance. Our results indicate that tumor-suppressor caveolin-1 is a core component of the Ca 2 þ -dependent apoptotic pathway and participates in the regulation of critical mitochondrial functions during tumor development. The compromised caveolin-1/Ca 2 þ axis contributes to failure in both mitochondrial metabolism and apoptosis, thereby sustaining the neoplastic phenotype. These results illustrate a direct link between Ca 2 þ regulation and mitochondrial biology in cancer.
Oncogene, 2019
Metformin is a hypoglycaemic agent used to treat type 2 diabetes mellitus (DM2) patients, with a ... more Metformin is a hypoglycaemic agent used to treat type 2 diabetes mellitus (DM2) patients, with a broad safety profile. Since previous epidemiological studies had shown that the incidence of hepatocellular carcinoma (HCC) decreased significantly in metformin treated DM2 patients, we hypothesised that intervention with metformin could reduce the risk of neoplastic transformation of hepatocytes. HCC is the most common primary liver malignancy and it generally originates in a background of liver fibrosis and cirrhosis. In the present study, we took advantage of a transgenic mouse (TG221) characterized by microRNA-221 overexpression, with cirrhotic liver background induced by chronic administration of carbon tetrachloride (CCl4). This mouse model develops fibrosis, cirrhosis and liver tumours that become visible in 100% of mice at 5-6 months of age. Our results demonstrated that metformin intervention improves liver function, inhibits hepatic stellate cell (HSC) activation, reduces liver fibrosis, depletes lipid accumulation in hepatocytes, halts progression to decompensated cirrhosis and abrogates development HCC in CCl4 challenged transgenic mouse model. The study establishes the rationale for investigating metformin in cirrhotic patients regardless of concomitant DM2 status. 28 background of chronic liver disease and cirrhosis, which 29 represents the most important risk factor for HCC [2]. Q4 The 30 extended time of progression from liver fibrosis to malig-31 nancy make individuals at risk for HCC identifiable and 32 candidates for chemoprevention strategies to delay or stop 33 the natural course of chronic liver disease and curtail HCC 34 incidence and mortality [3]. Q5 35 Hepatitis B vaccination programs or anti-hepatitis C 36 therapeutics are examples of approaches that not only pro-37 tect from viral infection, but also reduce the incidence of 38 virus-associated HCC [4, 5]. However, non-viral causes 39 namely alcoholic or non-alcoholic fatty liver disease 40 (NAFLD) and non-alcoholic steatohepatitis Q6 (NASH) 41 account for nearly 46% liver cancer deaths [6]. Addition-42 ally, increasing epidemic of obesity and type 2 diabetes 43 mellitus (DM2), both important risk factors of NAFLD and 44 NASH, might emerge as dominant risk factors for HCC 45 incidence in future [7, 8]. Hence, prevention programs can 46 have an important impact in decreasing HCC occurrence. 47 Metformin is a first-line dimethylbiguanide hypogly-48 caemic agent used to treat DM2 patients, with a broad safety 49 profile. Abundant epidemiological data have indicated that 50 incidence of several cancers, including HCC decreased
European Psychiatry
Antipsychotic drugs are currently used in clinical practice for a variety of mental disorders. Cl... more Antipsychotic drugs are currently used in clinical practice for a variety of mental disorders. Clozapine is the most effective medication for treatment-resistant schizophrenia, in controlling aggression and suicidal behavior in psychosis. Although clozapine is associated with a low likelihood of extrapyramidal symptoms and other neurological side effects, weight gain and metabolic side effects are well known in clinical practice exposing the patient to a greater risk of cardiovascular disorders, premature death, as well as psychosocial issues leading to non-adherence. The mechanisms underlying this pharmacologically activated disorders are still controversial. Based on our in vitro results, we have characterized in vivo the effects of the selective PKCβ inhibitor, Ruboxistaurin (LY-333531) on a preclinical model of long-term clozapine-induced weight gain. Cell biology, biochemistry and psychomotor tests have been performed on wild type and PKCβ (-/-) mutant mice to investigate the c...
Drugs that target human thymidylate synthase (hTS) are widely used in anti-cancer therapy. Howeve... more Drugs that target human thymidylate synthase (hTS) are widely used in anti-cancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces its over-expression and the development of drug resistance. We thus pursued an alternative strategy that led to the discovery of TS-dimer disrupters that bind at the monomer-monomer interface and shift the dimerization equilibrium of both the recombinant and the intracellular protein toward the inactive monomers. We performed a structural, spectroscopic and kinetic investigation of the effects of these small molecules andthe best one, E7, accelerates the proteasomal degradation of hTS in cancer cells. E7 showed a superior anticancer profile to fluorouracil in a mouse model of human pancreatic and ovarian cancer. Thus, over sixty years after the discovery of the first TS prodrug inhibitor, fluorouracil, E7 breaks the link between TS inhibition and enhanced expression in response, providing a strategy to fight drug-r...
Chirurgia italiana
The preservation of livers to be transplanted is currently obtained by static cold storage at 4 C... more The preservation of livers to be transplanted is currently obtained by static cold storage at 4 C degrees and flushing with UW solution. New methods of preservation are being studied that take advantage of machines for continuous hypothermic perfusion of the organ. Such machines have permitted a lengthening of preservation times and the use of livers from non-beating-heart donors. In an attempt to eliminate the damage due to hypothermia, to lengthen preservation times, and to extend the availability of livers to be transplanted, also using those subjected to short periods of warm ischaemia, we have constructed a transportable machine that produces a hyperbaric atmosphere and allows continuous perfusion of the liver. Ten pig livers from beating-heart donors were perfused with Ringer solution in hyperbaric conditions with oxygen at temperatures ranging from 10 to 25 degrees C for periods of up to 24 hours and studied by means of histopathological analysis and tests of mitochondrial ac...
Annals of the New York Academy of Sciences, 2007
In mammals, four different genes encode four PMCA isoforms. PMCA1 and PMCA4 are expressed ubiquit... more In mammals, four different genes encode four PMCA isoforms. PMCA1 and PMCA4 are expressed ubiquitously. PMCA2 and PMCA3 are expressed prevalently in the central nervous systems. More than 30 variants are generated by mechanisms of alternative splicing. The physiological meaning of the existence of such elevated number of isoforms is not clear, but it would be plausible to relate it to the cell-specific demands of Ca 2+ homeostasis. To characterize functional specificity of PMCA variants we have investigated two aspects: the effects of the overexpression of the different PMCA variants on cellular Ca 2+ handling and the existence of possible isoform-specific interactions with partner proteins using a yeast two-hybrid technique. The four basic PMCA isoforms were coexpressed in CHO cells together with the Ca 2+ -sensitive recombinant photoprotein aequorin. The effects of their overexpression on Ca 2+ homeostasis were monitored in the living cells. They had revealed that the ubiquitous isoforms 1 and 4 are less effective in reducing the Ca 2+ peaks generated by cell stimulation as compared to the neuronspecific isoforms 2 and 3. To establish whether these differences were related to different and new physiological regulators of the pump, the 90 N-terminal residues of PMCA2 and PMCA4 have been used as baits for the search of molecular partners. Screening of a human brain cDNA library with the PMCA4 bait specified the -isoform of protein 14-3-3, whereas no 14-3-3 clone was obtained with the PMCA2 bait. Overexpression of PMCA4/14-3-3 (but not of PMCA2/14-3-3 ) in HeLa cells together with targeted aequorins showed that the ability of the cells to export Ca 2+ was impaired. Thus, the interaction with 14-3-3 inhibited PMCA4 but not PMCA2. The role of PMCA2 has been further characterized by Ca 2+ measurements in cells overexpressing different splicing variants. The results indicated that the combination of alternative
EMBO molecular medicine, Jan 28, 2015
Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately ... more Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately 0.3-0.5% of the population and is characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhages. Cerebral cavernous malformation is a genetic disease that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Causative loss-of-function mutations have been identified in three genes, KRIT1 (CCM1), CCM2 (MGC4607), and PDCD10 (CCM3), which occur in both sporadic and familial forms. Autophagy is a bulk degradation process that maintains intracellular homeostasis and that plays essential quality control functions within the cell. Indeed, several studies have identified the association between dysregulated autophagy and different human diseases. Here, we show that the ablation of the KRIT1 gene strongly suppresses autophagy, leading to the abe...
Cell death & disease, 2012
Ca²⁺ transfer from endoplasmic reticulum (ER) to mitochondria can trigger apoptotic pathways by i... more Ca²⁺ transfer from endoplasmic reticulum (ER) to mitochondria can trigger apoptotic pathways by inducing release of mitochondrial pro-apoptotic factors. Three different types of inositol 1,4,5-trisphosphate receptor (IP₃R) serve to discharge Ca²⁺ from ER, but possess some peculiarities, especially in apoptosis induction. The anti-apoptotic protein Akt can phosphorylate all IP₃R isoforms and protect cells from apoptosis, reducing ER Ca²⁺ release. However, it has not been elucidated which IP₃R subtypes mediate these effects. Here, we show that Akt activation in COS7 cells, which lack of IP₃R I, strongly suppresses IP₃-mediated Ca²⁺ release and apoptosis. Conversely, in SH-SY 5Y cells, which are type III-deficient, Akt is unable to modulate ER Ca²⁺ flux, losing its anti-apoptotic activity. In SH-SY 5Y-expressing subtype III, Akt recovers its protective function on cell death, by reduction of Ca²⁺ release. Moreover, regulating Ca²⁺ flux to mitochondria, Akt maintains the mitochondrial i...
Frontiers in Oncology, 2013
Atypical protein kinase C isoforms are serine threonine kinases involved in various pathological ... more Atypical protein kinase C isoforms are serine threonine kinases involved in various pathological conditions. In recent years, the PKCζ isoform has emerged as an important regulator of multiple cellular processes operating in cancer. In this review, we will focus on the PKCζ isoform as an oxidative-sensing kinase involved in cancer-related inflammation and chemoresistance. We will discuss its nuclear localization and its possible pivotal role in connecting inflammation with drug resistance.
Novartis Foundation Symposia, 2007
PA-GFP: a window into the subcellular adventures of the individual mitochondrion 21 Discussion 36... more PA-GFP: a window into the subcellular adventures of the individual mitochondrion 21 Discussion 36 Luca Scorrano Multiple functions of mitochondria-shaping proteins 47 Discussion 55 Bruce M. Spiegelman Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators 60
Methods in Cell Biology, 2007
Science, 2007
human tracheal epithelial cells expressing high amounts of terminal a2,6 SA motifs and, simultane... more human tracheal epithelial cells expressing high amounts of terminal a2,6 SA motifs and, simultaneously, in an improved ability to overcome the inhibitory effects of human bronchial mucins associated with a2,3 SA receptors (28). However, mutations that caused a shift from the avian-type to human-type receptor binding specificity for the H1 subtype do not cause an equivalent shift in specificity for the H5 subtype (24). Likewise, the amino acid changes required to alter the H3 HA from an avian-to human-type receptor binding specificity are different from those required for the H1 HA. Therefore, it is likely that different avian HA subtypes have different structural requirements to confer receptor specificity. Thus, it is currently unknown which additional mutations in the H5 HAwould cause a shift to the human-type specificity, which may be required for H5N1 viruses to transmit efficiently among humans.
Purinergic Signalling, 2012
Since 1929, when it was discovered that ATP is a substrate for muscle contraction, the knowledge ... more Since 1929, when it was discovered that ATP is a substrate for muscle contraction, the knowledge about this purine nucleotide has been greatly expanded. Many aspects of cell metabolism revolve around ATP production and consumption. It is important to understand the concepts of glucose and oxygen consumption in aerobic and anaerobic life and to link bioenergetics with the vast amount of reactions occurring within cells. ATP is universally seen as the energy exchange factor that connects anabolism and catabolism but also fuels processes such as motile contraction, phosphorylations, and active transport. It is also a signalling molecule in the purinergic signalling mechanisms. In this review, we will discuss all the main mechanisms of ATP production linked to ADP phosphorylation as well the regulation of these mechanisms during stress conditions and in connection with calcium signalling events. Recent advances regarding ATP storage and its special significance for purinergic signalling will also be reviewed.
Proceedings of the National Academy of Sciences, 2008
Regeneration of mesenchymal tissues depends on a resident stem cell population, that in most case... more Regeneration of mesenchymal tissues depends on a resident stem cell population, that in most cases remains elusive in terms of cellular identity and differentiation signals. We here show that primary cell cultures derived from adipose tissue or skeletal muscle differentiate into adipocytes when cultured in high glucose. High glucose induces ROS production and PKC activation. These two events appear crucial steps in this differentiation process that can be directly induced by oxidizing agents and inhibited by PKC siRNA silencing. The differentiated adipocytes, when implanted in vivo, form viable and vascularized adipose tissue. Overall, the data highlight a previously uncharacterized differentiation route triggered by high glucose that drives not only resident stem cells of the adipose tissue but also uncommitted precursors present in muscle cells to form adipose depots. This process may represent a feed-forward cycle between the regional increase in adiposity and insulin resistance that plays a key role in the pathogenesis of diabetes mellitus.
Proceedings of the National Academy of Sciences, 2009
Despite the growing interest in the Fhit tumor suppressor protein, frequently deleted in human ca... more Despite the growing interest in the Fhit tumor suppressor protein, frequently deleted in human cancers, the mechanism of its powerful proapoptotic activity has remained elusive. We here demonstrate that Fhit sensitizes the low-affinity Ca(2+) transporters of mitochondria, enhancing Ca(2+) uptake into the organelle both in intact and in permabilized cells, and potentiating the effect of apoptotic agents. This effect can be attributed to the fraction of Fhit sorted to mitochondria, as a fully mitochondrial Fhit (a chimeric protein including a mitochondrial targeting sequence) retains the Ca(2+) signaling properties of Fhit and the proapoptotic activity of the native protein (whereas the effects on the cell cycle are lost). Thus, the partial sorting of Fhit to mitochondria allows to finely tune the sensitivity of the organelle to the highly pleiomorphic Ca(2+) signals, synergizing with apoptotic challenges. This concept, and the identification of the molecular machinery, may provide ways to act on apoptotic cell death and its derangement in cancer.
The Pharmacogenomics Journal, 2010
Atypical antipsychotics (APDs) are currently used in clinical practice for a variety of mental di... more Atypical antipsychotics (APDs) are currently used in clinical practice for a variety of mental disorders such as schizophrenia, bipolar disorder and severe behavioral disturbances. A well-known disadvantage of using these compounds is a propensity for weight gain, resulting frequently in obesity. The mechanisms underlying pharmacologically induced weight gain are still controversial. The objective of this study was to evaluate in vitro the effects of different APDs on adipogenic events in cultured human pre-adipocytes and in rat muscle-derived stem cells (MDSCs), aiming to identify a common intracellular event contributable to these drugs. Culture behavior was evaluated in terms of cell proliferation, lipid accumulation, gene expression and morphological features. Results indicate that APDs influence adipogenic events through changes in the differentiation and proliferation of preadipocytes and MDSCs that are brought on by protein kinase C-b (PKC-b) activation. These data identify a signaling route that could be a potential target of pharmacological approaches for preventing the weight gain associated with APD treatment.
Oncogene, 2014
A growing body of research has highlighted the complex range of tumoral traits acquired during H-... more A growing body of research has highlighted the complex range of tumoral traits acquired during H-Ras-driven transformation and maintenance, which include proliferative signaling, growth suppressor evasion and resistance to cell death. Clear molecular information about these processes is not yet available, but recent evidence has provided solid support for the importance of mitochondria. Here, we show that the induction of oncogenic H-Ras leads to changes in intracellular calcium (Ca 2 þ ), evaluate the temporal relationship between oncogene expression and mitochondrial physiology, and demonstrate that Ca 2 þ homeostasis is altered by caveolin-1, a protein that has a key role in tumor maintenance. Our results indicate that tumor-suppressor caveolin-1 is a core component of the Ca 2 þ -dependent apoptotic pathway and participates in the regulation of critical mitochondrial functions during tumor development. The compromised caveolin-1/Ca 2 þ axis contributes to failure in both mitochondrial metabolism and apoptosis, thereby sustaining the neoplastic phenotype. These results illustrate a direct link between Ca 2 þ regulation and mitochondrial biology in cancer.