Publications

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Mounting evidence links neurodegenerative disorders such as Parkinson and Alzheimer disease with mitochondrial dysfunction and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link emerged recently, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in post-mitotic tissues. Here, we report two Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.Methods Patients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, muscle and brain MR spectroscopy, analysis of muscle biopsy and fibroblasts. Candidate genes were sequenced and mtDNA was analyzed for rearrangements.ResultsAffected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed COX negative fibers and mtDNA multiple deletions, and MR spectroscopy displayed defective oxidative metabolism in muscle and brain. We found two heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the GTPase domain, each segregating with affected individuals. Fibroblast studies showed reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.InterpretationThe association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the link of defective mitochondrial dynamics, mtDNA multiple deletions and altered mitophagy with parkinsonism. This article is protected by copyright. All rights reserved.
    Annals of Neurology 03/2015; DOI:10.1002/ana.24410 · 11.91 Impact Factor
  • Source
    Cell cycle (Georgetown, Tex.) 02/2015; DOI:10.1080/15384101.2015.1010973 · 5.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The P2X7 receptor (P2X7R) is a known and powerful activator of the NOD-like receptor (NLR)P3 inflammasome; however, the underlying pathways are poorly understood. Thus, we investigated the molecular mechanisms involved. The effect of P2X7R expression and activation on NLRP3 expression and recruitment was investigated by Western blot, RT-PCR, coimmunoprecipitation, and confocal microscopy in microglial mouse cell lines selected for reduced P2X7R expression and in primary cells from P2X7R(-/-) C57BL/6 mice. We show here that P2X7R activation by ATP (EC50 = 1 mM) or benzoyl-ATP (EC50 = 300 μM) and P2X7R down-modulation caused a 2- to 8-fold up-regulation of NLRP3 mRNA in mouse N13 microglial cells. Moreover, NLRP3 mRNA was also up-regulated in primary microglial and macrophage cells from P2X7R(-/-) mice. Confocal microscopy and immunoprecipitation assays showed that P2X7R and NLRP3 closely interacted at discrete subplasmalemmal sites. Finally, P2X7R stimulation caused a transient (3-4 min) cytoplasmic Ca(2+) increase localized to small (2-3 µm wide) discrete subplasmalemmal regions. The Ca(2+) increase drove P2X7R recruitment and a 4-fold increase in P2X7R/NLRP3 association within 1-2 min. These data show a close P2X7R and NLRP3 interaction and highlight the role of P2X7R in the localized cytoplasmic ion changes responsible for both NLRP3 recruitment and activation.-Franceschini, A., Capece, M., Chiozzi, P., Falzoni, S., Sanz, J. M., Sarti, A. C., Bonora, M., Pinton, P., and Di Virgilio, F. The P2X7 receptor directly interacts with the NLRP3 inflammasome scaffold protein. © FASEB.
    The FASEB Journal 02/2015; DOI:10.1096/fj.14-268714 · 5.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The common pathological manifestation of cystic fibrosis (CF) is associated with an excessive lung inflammatory response characterized by interleukin-1β accumulation. CF airway epithelial cells show an exacerbated pro-inflammatory response to Pseudomonas aeruginosa; however, it is unclear whether this heightened inflammatory response is intrinsic to cells lacking CF transmembrane conductance regulator (CFTR). Here we demonstrate that the degree and quality of the inflammatory response in CF are supported by P. aeruginosa-dependent mitochondrial perturbation, in which flagellin is the inducer and mitochondrial Ca(2+) uniporter (MCU) is a signal-integrating organelle member for NLRP3 activation and IL-1β and IL-18 processing. Our work elucidates the regulation of the NLRP3 inflammasome by mitochondrial Ca(2+) in the P. aeruginosa-dependent inflammatory response and deepens our understanding of the significance of mitochondria in the Ca(2+)-dependent control of inflammation.
    Nature Communications 02/2015; 6:6201. DOI:10.1038/ncomms7201 · 10.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The tumor suppressor p53 is a key protein in preventing cell transformation and tumor progression. Activated by a variety of stimuli, p53 regulates cell-cycle arrest and apoptosis. Along with its well-documented transcriptional control over cell-death programs within the nucleus, p53 exerts crucial although still poorly understood functions in the cytoplasm, directly modulating the apoptotic response at the mitochondrial level. Calcium (Ca(2+)) transfer between the endoplasmic reticulum (ER) and mitochondria represents a critical signal in the induction of apoptosis. However, the mechanism controlling this flux in response to stress stimuli remains largely unknown. Here we show that, in the cytoplasm, WT p53 localizes at the ER and at specialized contact domains between the ER and mitochondria (mitochondria-associated membranes). We demonstrate that, upon stress stimuli, WT p53 accumulates at these sites and modulates Ca(2+) homeostasis. Mechanistically, upon activation, WT p53 directly binds to the sarco/ER Ca(2+)-ATPase (SERCA) pump at the ER, changing its oxidative state and thus leading to an increased Ca(2+) load, followed by an enhanced transfer to mitochondria. The consequent mitochondrial Ca(2+) overload causes in turn alterations in the morphology of this organelle and induction of apoptosis. Pharmacological inactivation of WT p53 or naturally occurring p53 missense mutants inhibits SERCA pump activity at the ER, leading to a reduction of the Ca(2+) signaling from the ER to mitochondria. These findings define a critical nonnuclear function of p53 in regulating Ca(2+) signal-dependent apoptosis.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nicotinic acid adenine dinucleotide phosphate (NAADP) serves as the ideal trigger of spatio-temporally complex intracellular Ca2+ signals. However, the identity of the intracellular Ca2+ store(s) recruited by NAADP, which may include either the endolysosomal (EL) or the endoplasmic reticulum (ER) Ca2+ pools, is still elusive. Here, we show that the Ca2+ response to NAADP was suppressed by interfering with either EL or ER Ca2+ sequestration. The measurement of EL and ER Ca2+ levels by using selectively targeted aequorin unveiled that the preventing ER Ca2+ storage also affected ER Ca2+ loading and viceversa. This indicates that a functional Ca2+-mediated cross-talk exists at the EL-ER interface and exerts profound implications for the study of NAADP-induced Ca2+ signals. Extreme caution is warranted when dissecting NAADP targets by pharmacologically inhibiting EL and/or the ER Ca2+ pools. Moreover, Ca2+ transfer between these compartments might be essential to regulate vital Ca2+-dependent processes in both organelles.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Significance: in all cells, the endoplasmic reticulum (ER) and mitochondria are physically connected to form junctions termed mitochondria-associated membranes (MAMs). This subcellular compartment is under intense investigation because it represents a "hot spot" for the intracellular signaling of important pathways, including the synthesis of cholesterol and phospholipids, calcium homeostasis and reactive oxygen species (ROS) generation and activity. Recent advances: the advanced methods currently used to study this fascinating intracellular microdomain in detail have enabled the identification of the molecular composition of MAMs and their involvement within different physiopathological contexts. Critical issues: here we review the knowledge regarding i) MAMs composition in terms of protein composition, ii) the relationship between MAMs and ROS, iii) the involvement of MAMs in cell death programs with particular emphasis within the tumor context, iv) the emerging role of MAMs during inflammation and v) the key role of MAMs alterations in selected neurological disorders. Future directions: whether alterations in MAMs represent a response to the disease pathogenesis or directly contribute to the disease has not yet been unequivocally established. In any case, the signaling at the MAMs represent a promising pharmacological target for several important human diseases.
    Antioxidants and Redox Signaling 01/2015; DOI:10.1089/ars.2014.6223 · 7.67 Impact Factor
  • Source
    Simone Patergnani, Paolo Pinton
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria are highly dynamic organelles, with a morphology ranging from small roundish elements to large interconnected networks. This fine architecture has a significant impact on mitochondrial homeostasis, and mitochondrial morphology is highly connected to specific cellular process. Autophagy is a catabolic process in which cell constituents, including proteins and organelles, are delivered to the lysosomal compartment for degradation. Autophagy has multiple physiological functions and recent advances have demonstrated that this process is linked to different human diseases, such as cancer and neurodegenerative disorders.In particular, it has been found that autophagy is a key determinant for the life span of mitochondria through a particularly fine-tuned mechanism called mitophagy, a selective form of autophagy, which ensures the preservation of healthy mitochondria through the removal of damaged or superfluous mitochondria. Mitophagy has been found to be altered in several pathologies and aberrant or excessive levels of this process are found in common human disorders. Thus, the measurement of the mitophagy levels is of fundamental relevance to elucidate the molecular mechanism of this process and, most importantly, its role in cellular homeostasis and disease.In this review, we will provide an overview of the current methods used to measure mitophagic levels, with particular emphasis on the techniques based on fluorescent probes.
    Methods in Molecular Biology 01/2015; 1241:181-94. DOI:10.1007/978-1-4939-1875-1_15 · 1.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The adaptor protein p66Shc links membrane receptors to intracellular signalling pathways and has the potential to respond to energy status changes and regulate mitogenic signalling. Initially reported to mediate growth signals in normal and cancer cells, p66Shc has also been recognized as a pro-apoptotic protein involved in the cellular response to oxidative stress. Moreover, it is a key element in processes such as cancer cell proliferation, tumor progression, metastasis and metabolic reprogramming. Recent findings on the role of p66Shc in the above-mentioned processes have been obtained through the use of various tumor cell types, including prostate, breast, ovarian, lung, colon, skin and thyroid cancer cells. Interestingly, the impact of p66Shc on the proliferation rate was mainly observed in prostate tumors, while its impact on metastasis was mainly found in breast cancers. In this review, we summarize the current knowledge about the possible roles of p66Shc in different cancers.
    European Journal of Clinical Investigation 01/2015; 45(s1). DOI:10.1111/eci.12364 · 2.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The ATP receptor P2X7 (P2X7R or P2RX7) has a key role in inflammation and immunity, but its possible roles in cancer are not firmly established. In the present study we investigated the effect of host genetic deletion of P2X7R in the mouse on the growth of B16 melanoma or CT26 colon carcinoma cells. Tumor size and metastatic dissemination were assessed by in vivo calliper and luciferase luminescence emission measurements along with post-mortem examination. In P2X7R-deficient mice, tumor growth and metastatic spreading were accelerated strongly compared to wild-type (wt) mice. Intratumoral IL-1ß and VEGF release were drastically reduced and inflammatory cell infiltration was abrogated nearly completely. Similarly, tumor growth was also greatly accelerated in wt chimeric mice implanted with P2X7R-deficient bone-marrow cells, defining hematopoietic cells as a sufficient site of P2X7R action. Finally, dendritic cells (DCs) from P2X7R-deficient mice were unresponsive to stimulation with tumor cells, and chemotaxis of P2X7R-less cells was impaired. Overall, our results showed that host P2X7R expression was critical to support an anti-tumor immune response, and to restrict tumor growth and metastatic diffusion. Copyright © 2014, American Association for Cancer Research.
    Cancer Research 12/2014; 75(4). DOI:10.1158/0008-5472.CAN-14-1259 · 9.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: One challenge in biology is signal transduction monitoring in a physiological context. Intravital imaging techniques are revolutionizing our understanding of tumor and host cell behaviors in the tumor environment. However, these deep tissue imaging techniques have not yet been adopted to investigate the second messenger calcium (Ca2+). In the present study, we established conditions that allow the in vivo detection of Ca2+ signaling in three-dimensional tumor masses in mouse models. By combining intravital imaging and a skinfold chamber technique, we determined the ability of photodynamic cancer therapy to induce an increase in intracellular Ca2+ concentrations and, consequently, an increase in cell death in a p53-dependent pathway.
    Oncotarget 12/2014; · 6.63 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Selenoprotein N (SEPN1), is a broadly expressed resident protein of the endoplasmic reticulum (ER) whose loss-of-function inexplicably leads to human muscle disease. We found that SEPN1 levels parallel those of endoplamic reticulum oxidoreductin 1 (ERO1), an ER protein thiol oxidase, and that SEPN1's redox activity defends the ER from ERO1-generated peroxides. Moreover, we have defined the redox-regulated interactome of SEPN1 and identified the ER calcium import SERCA2 pump as a redox-partner of SEPN1. SEPN1 enhances SERCA2 activity by reducing luminal cysteines that are hyperoxidised by ERO1-generated peroxides. Cells lacking SEPN1 are hypersensitive to ERO1 overexpression and conspicuously defective in ER calcium re-uptake. After being muscle-transduced with an adeno-associated virus driving ERO1α SEPN1 knockout mice unmasks a myopathy that resembles the dense core disease due to human mutations in SEPN1, whereas the combined attenuation of ERO1α and SEPN1 enhances cell fitness. These observations reveal the involvement of SEPN1 in ER redox and calcium homeostasis and that an ERO1 inhibitor, restoring redox-dependent calcium homeostasis, may ameliorate the myopathy of SEPN1 deficiency. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 12/2014; DOI:10.1093/hmg/ddu602 · 6.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 2 Equipe 11 labelis ee par la Ligue Nationale contre le cancer, A lavian and colleagues recently pro-vided further evidence in support of the notion that the c subunit of the mito-chondrial F 1 F O ATP synthase constitutes the long-sought pore-forming unit of the supramolecular complex responsible for the so-called 'mitochondrial permeability transition' (MPT). Besides shedding new light on the molecular mechanisms that underlie the MPT, these findings corrob-orate the notion that several components of the cell death machinery, including cytochrome c and the F 1 F O ATP syn-thase, mediate critical metabolic activities. The term 'mitochondrial permeability transition' (MPT) is generally employed to indicate an abrupt increase of the perme-ability of the inner mitochondrial mem-brane (IMM) to small solutes. This results not only in the immediate dissipation of the mitochondrial transmembrane poten-tial (Dc m), and hence in the arrest of mito-chondrial ATP synthesis, but also in a profound ionic imbalance that provokes the osmotic breakdown of the organelle.
    Cell cycle (Georgetown, Tex.) 11/2014; 13(17):2666--2670. DOI:10.4161/15384101.2014.949082 · 5.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hailey-Hailey disease (HHD), also known as familial benign chronic pemphigus, is a rare autosomal dominant inherited intraepidermal blistering genodermatosis. Mutations in the ATP2C1 gene encoding for the Golgi secretory pathway Ca(2+) /Mn(2+) -ATPasi protein 1 (SPCA1) affect the processing of desmosomal components and the epidermal suprabasal cell-cell adhesion by deregulating the keratinocyte cytosolic Ca(2+) concentration. We report the unexpected, dramatic, and persistent clinical improvement of the skin lesions of a patient affected with longstanding HHD with daily intake of a solution containing magnesium chloride hexahydrate (MgCl2 ). We investigated the effect of MgCl2 on the intracellular Ca(2+) homeostasis and on the activity of particular Ca(2+) -effectors in HeLa cells transfected with chimeric aequorins (cytAEQ, mtAEQ, erAEQ and GoAEQ) targeted to different subcellular compartments (cytosol, mitochondria, endoplasmic reticulum, and Golgi, respectively). Experimental investigations on HeLa cells showed the effect of MgCl2 on the function of Ca(2+) -extrusor systems, resulting in increased cytosolic and mitochondrial Ca(2+) levels, without altering the mechanisms of intraluminal Ca(2+) -filling and Ca(2+) -release of stores. Based on our clinical observation and experimental results, it can be hypothesized that MgCl2 could act as an inhibitor of the Ca(2+) -extruding activity in keratinocytes favoring intracellular Ca(2+) -disponibility and Ca(2+) -dependent mechanisms in desmosome assembly. This may represent the molecular basis of the good response of the HHD clinical features with MgCl2 solution in the patient described. © 2014 The International Society of Dermatology.
    International journal of dermatology 11/2014; DOI:10.1111/ijd.12410 · 1.23 Impact Factor
  • Source
    Massimo Bonora, Paolo Pinton
    [Show abstract] [Hide abstract]
    ABSTRACT: Since its discovery in the 1970s, the mitochondrial permeability transition (MPT) has been proposed to be a strategic regulator of cell death. Intense research efforts have focused on elucidating the molecular components of the MPT because this knowledge may help to better understand and treat various pathologies ranging from neurodegenerative and cardiac diseases to cancer. In the case of cancer, several studies have revealed alterations in the activity of the mitochondrial permeability transition pore (mPTP) and have determined its regulatory mechanism; these studies have also suggested that suppression of the activity of the mPTP, rather than its inactivation, commonly occurs in solid neoplasms. This review focuses on the most recent advances in understanding mPTP regulation in cancer and highlights the ability of the mPTP to impede the mechanisms of cell death.
    Frontiers in Oncology 11/2014; 4:302. DOI:10.3389/fonc.2014.00302
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Structural fat grafting utilizes the centrifugation of liposuction aspirates to create a graded density of adipose tissue. This study was performed to qualitatively investigate the effects of centrifugation on stem cells present in adipose tissue. Liposuction aspirates were obtained from healthy donors and either not centrifuged or centrifuged at 1,800 rpm for 3 minutes. The obtained fat volumes were divided into three layers and then analyzed. The results demonstrate that centrifugation induces a different distribution of stem cells in the three layers. The high-density layer displays the highest expression of mesenchymal stem cell and endothelial markers. The low-density layer exhibits an enrichment of multipotent stem cells. We conclude that appropriate centrifugation concentrates stem cells. This finding may influence the clinical practice of liposuction aspirate centrifugation and enhance graft uptake.
    PLoS ONE 11/2014; 9(11):e110796. DOI:10.1371/journal.pone.0110796 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Renal cell carcinoma is a common neoplasia of the adult kidney that accounts for about 3% of adult malignancies. Clear cell renal carcinoma is the most frequent subtype of kidney cancer and 20–40% of patients develop metastases. The absence of appropriate biomarkers complicates diagnosis and prognosis of this disease. In this regard, small noncoding RNAs (microRNAs), which are mutated in several neoplastic diseases including kidney carcinoma, may be optimal candidates as biomarkers for diagnosis and prognosis of this kind of cancer. Here we show that patients with clear cell kidney carcinoma that express low levels of miR501-5p exhibited a good prognosis compared with patients with unchanged or high levels of this microRNA. Consistently, in kidney carcinoma cells the downregulation of miR501-5p induced an increased caspase-3 activity, p53 expression as well as decreased mTOR activation, leading to stimulation of the apoptotic pathway. Conversely, miR501-5p upregulation enhanced the activity of mTOR and promoted both cell proliferation and survival. These biological processes occurred through p53 inactivation by proteasome degradation in a mechanism involving MDM2-mediated p53 ubiquitination. Our results support a role for miR501-5p in balancing apoptosis and cell survival in clear cell renal carcinoma. In particular, the downregulation of microRNA501-5p promotes a good prognosis, while its upregulation contributes to a poor prognosis, in particular, if associated with p53 and MDM2 overexpression and mTOR activation. Thus, the expression of miR501-5p is a possible biomarker for the prognosis of clear cell renal carcinoma.
    11/2014; 4. DOI:10.1016/j.fob.2014.10.016
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare movement disorder characterized by sudden attacks of involuntary movements. Familial PNKD is an autosomal dominant trait, caused by mutations in the myofibrillogenesis regulator 1 (MR-1) gene on chromosome 2q35. Three different mutations have been described; all of them reside in the N-terminal region common to isoforms L and S, that has been suggested to code for a mitochondrial targeting sequence, necessary for the correct sub-cellular localization of the protein into mitochondria. We report on four patients of the same family, affected by PNKD. Skin fibroblasts were used to analysed oxygen consumption and to measure mitochondrial matrix calcium response after agonist stimulation. Mitotracker-based visualization was also used to assess fragmentation of the mitochondrial network. the paroxysmal movements were dystonic in two patients and dystonic/choreiform in the other ones; in three cases the symptoms started in one limb and then generalized, while in one case remained focal. Three had a very early onset, within the first two years of life. The frequency of episodes showed a great variability, ranging from 2 times a day to 3 times a year, while the duration of the attacks ranged from 2 min to 1,5 h, always with sudden onset and end and complete recover in between. All affected subjects harbored a heterozygous C to T substitution in MR-1, causing an Ala9Val amino acid change in the N-terminal region. A significant reduction of oxygen consumption and altered calcium homeostasis were found in mutant fibroblasts compared to controls, while no difference was detected in mitochondrial network. The data on reduced oxygen consumption and altered calcium homeostasis obtained on mutant fibroblasts are the first evidences, in physiological conditions, of a mitochondrial dysfunction in PNKD. Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
    European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 10/2014; 19(1). DOI:10.1016/j.ejpn.2014.10.003 · 1.93 Impact Factor
  • Source
    Massimo Bonora, Paolo Pinton
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial F1/F0 ATP synthase is one of the most intensively studied enzymatic complexes because of the nature of its molecular machinery and the role that it plays in regulating a cell's life in terms of ATP synthesis. In recent years, it has been proposed that this molecular complex could play an unexpected role in cell death, especially in the mitochondrial permeability transition pore (mPTP).
    Mitochondrion 10/2014; 21. DOI:10.1016/j.mito.2014.10.001 · 3.52 Impact Factor
  • Source
    Angela Bononi, Paolo Pinton
    [Show abstract] [Hide abstract]
    ABSTRACT: The tumor suppressor PTEN is a key regulator of a plethora of cellular processes that are crucial in cancer development. Through its lipid phosphatase activity PTEN suppresses the PI3K/AKT pathway to govern cell proliferation, growth, migration, energy metabolism and death. The repertoire of roles fulfilled by PTEN has recently been expanded to include crucial functions in the nucleus, where it favors genomic stability and restrains cell cycle progression, as well as protein phosphatase dependent activity at the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs), where PTEN interacts with the inositol 1,4,5-trisphosphate receptors (IP3Rs) and regulates Ca(2+) release from the ER and sensitivity to apoptosis. Indeed, PTEN is present in definite subcellular locations where it performs distinct functions acting on specific effectors. In this review, we summarize recent advantages in methods to study PTEN subcellular localization and the distinct biological functions of PTEN in different cellular compartments. A deeper understanding of PTEN's compartmentalized-functions will guide the rational design of novel therapies.
    Methods 10/2014; DOI:10.1016/j.ymeth.2014.10.002 · 3.22 Impact Factor

989 Following View all

431 Followers View all