Human Axonal Survival of Motor Neuron (a-SMN) Protein Stimulates Axon Growth, Cell Motility, C-C Motif Ligand 2 (CCL2), and Insulin-like Growth Factor-1 (IGF1) Production

Locatelli, Denise; Terao, Mineko; Fratelli, Maddalena; Zanetti, Adriana; Kurosaki, Mami; Lupi, Monica; Barzago, Maria Monica; Uggetti, Andrea; Capra, Silvia; d’Errico, Paolo; Battaglia, Giorgio; Garattini, Enrico

doi:10.1074/jbc.m112.362830

Cited by 27 publications

(28 citation statements)

References 63 publications

(70 reference statements)

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“…These markers and many others in the biomarker candidate list (Table 1) are members of RTK/mTOR, STAT, TGFB/SMAD/BMP or p21 pathways that have been published in SMA cellular, invertebrate, and mouse models as modulators of disease phenotype and SMN [28], [29], [56]–[60]. Some analytes probed had been identified as possible SMA therapeutic targets or biomarkers: CCL2, GLO1, IGF1, and PRL [28]–[31], [61], [62]. These potential PD markers require analysis in an SMN-upregulating in vivo treatment paradigm.…”

Section: Discussionmentioning

confidence: 99%

SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

et al. 2013

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ObjectivesSpinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS).MethodsBforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores.Results12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13th analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures.ConclusionsDiscovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.

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Section: Discussionmentioning

confidence: 99%

SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

et al. 2013

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“…The insulin growth factor (IGF) pathway is activated in several malignancies including HCC [11,12]. In addition, signaling through IGF1 is essential for normal development and growth [13]. Through downstream activation of both PI3K/ AKT and MAPK/ERK kinase, IGF1 controls cell proliferation and survival, respectively [14,15].…”

Section: Introductionmentioning

confidence: 99%

Down-regulated miR-28-5p in human hepatocellular carcinoma correlated with tumor proliferation and migration by targeting insulin-like growth factor-1 (IGF-1)

Shi

Teng

2015

Mol Cell Biochem

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Hepatocellular carcinoma (HCC) is a rapidly progressing, incurable cancer that frequently spreads to portal vein and lung. New insights are needed to identify therapeutic targets to prevent or retard HCC metastatic progression. Because microRNAs (miRNA) often act as tumor regulators, we investigated their role in preclinical models of HCC. Here we found miR-28-5p is a liver-relevant anti-proliferative miRNA whose expression, functions, and mechanisms were analyzed in human hepatoma cells, HepG2 and Huh7. Interestingly, when evaluating the specific targets of miR-28-5p, we found that ectopic miR-28-5p expression down-regulates insulin-like growth factor 1 (IGF1) protein and that the expression of miR-28-5p correlates negatively with IGF1 protein in HCC cells. Luciferase report in HCC cells expressing miR-28-5p suggests that miR-28-5p reduces luciferase activity by targeting the 3'-UTR of IGF1 mRNA. Additionally, we show that the selective inhibition of either the PI3K/AKT pathway prior to miR-28-5p stimulation prevents the expression of previously described tumor suppressor miRNAs that are family and cluster specific. Together, our results defined miR-28-5p as a critical regulator of IGF1 mRNA translation function, down-regulated miR-28-5p in HCC was associated with tumor growth through PI3K/AKT pathway by targeting IGF1. miR-28-5p-IGF1-PI3K/AKT pathway may play an important role in the development of HCC.

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“…Second, the link between a-SMN and SMA is uncertain [ 32 ], even if the disruption of the a-SMN axonogenic properties by SMA mutations might suggest a role in SMA pathogenesis [ 14 ]. Finally, it is not as yet clear whether a-SMN might act in concert with FL-SMN, even if the potential mediators of a-SMN biological activity in axon growth and cell motility, i.e., the CCL2 and CCL7 chemokines and the growth factor IGF1, might indicate a cell role of a-SMN distinct from that of FL-SMN [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Different Stability and Proteasome-Mediated Degradation Rate of SMN Protein Isoforms

et al. 2015

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The key pathogenic steps leading to spinal muscular atrophy (SMA), a genetic disease characterized by selective motor neuron degeneration, are not fully clarified. The full-length SMN protein (FL-SMN), the main protein product of the disease gene SMN1, plays an established role in the cytoplasm in snRNP biogenesis ultimately leading to mRNA splicing within the nucleus. It is also involved in the mRNA axonal transport. However, to what extent the impairment of these two SMN functions contributes to SMA pathogenesis remains unknown. A shorter SMN isoform, axonal-SMN or a-SMN, with more specific axonal localization, has been discovered, but whether it might act in concert with FL-SMN in SMA pathogenesis is not known. As a first step in defining common or divergent intracellular roles of FL-SMN vs a-SMN proteins, we here characterized the turn-over of both proteins and investigated which pathway contributed to a-SMN degradation. We performed real time western blot and confocal immunofluorescence analysis in easily controllable in vitro settings. We analyzed co-transfected NSC34 and HeLa cells and cell clones stably expressing both a-SMN and FL-SMN proteins after specific blocking of transcript or protein synthesis and inhibition of known intracellular degradation pathways. Our data indicated that whereas the stability of both FL-SMN and a-SMN transcripts was comparable, the a-SMN protein was characterized by a much shorter half-life than FL-SMN. In addition, as already demonstrated for FL-SMN, the Ub/proteasome pathway played a major role in the a-SMN protein degradation. We hypothesize that the faster degradation rate of a-SMN vs FL-SMN is related to the protection provided by the protein complex in which FL-SMN is assembled. The diverse a-SMN vs FL-SMN C-terminus may dictate different protein interactions and complex formation explaining the different localization and role in the neuronal compartment, and the lower expression and stability of a-SMN.

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Human Axonal Survival of Motor Neuron (a-SMN) Protein Stimulates Axon Growth, Cell Motility, C-C Motif Ligand 2 (CCL2), and Insulin-like Growth Factor-1 (IGF1) Production

Cited by 27 publications

References 63 publications

SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

Down-regulated miR-28-5p in human hepatocellular carcinoma correlated with tumor proliferation and migration by targeting insulin-like growth factor-1 (IGF-1)

Different Stability and Proteasome-Mediated Degradation Rate of SMN Protein Isoforms

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