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Ilaria Penna, Irene Vassallo,
Mario Nizzari,
Debora Russo,
Delfina Costa,
Paola Menichini,
Alessandro Poggi,
Claudio Russo,
Giorgio Dieci,
Tullio Florio,
Ranieri Cancedda,
Aldo Pagano
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ABSTRACT: FE65 proteins constitute a family of adaptors which modulates the processing of amyloid precursor protein (APP) and the consequent amyloid β production. Thus, they have been involved in the complex and partially unknown cascade of reactions at the base of Alzheimer's disease (AD) etiology. However, FE65 and FE65-like (APBB2) proteins may be linked to neurodegeneration through the regulation of cell cycle in post-mitotic neurons. In this work we disclose novel molecular mechanisms by which APBB2 can modulate APP processing. We show that APBB2 mRNA splicing, driven by the over-expression of a novel non-coding (nc) RNA named 45A, allow the generation of alternative protein forms endowed with differential effects on Aβ production, cell cycle control, and DNA damage response. 45A overexpression also favors cell transformation and tumorigenesis leading to a marked increase of malignancy of neuroblastoma cells. Therefore, our results highlight a novel regulatory pathway of considerable interest linking APP processing with cell cycle regulation and DNA-surveillance systems, that may represent a molecular mechanism to induce neurodegeneration in post-mitotic neurons.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 06/2013; 1833(6):1511-1526. · 5.54 Impact Factor
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Sara Massone, Irene Vassallo,
Manuele Castelnuovo,
Gloria Fiorino,
Elena Gatta,
Mauro Robello,
Roberta Borghi,
Massimo Tabaton,
Claudio Russo,
Giorgio Dieci,
Ranieri Cancedda,
Aldo Pagano
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ABSTRACT: Alternative splicing generates protein isoforms that are conditionally or differentially expressed in specific tissues. The discovery of factors that control alternative splicing might clarify the molecular basis of biological and pathological processes. We found that IL1-α-dependent up-regulation of 38A, a small ribonucleic acid (RNA) polymerase III-transcribed RNA, drives the synthesis of an alternatively spliced form of the potassium channel-interacting protein (KCNIP4). The alternative KCNIP4 isoform cannot interact with the γ-secretase complex, resulting in modification of γ-secretase activity, amyloid precursor protein processing, and increased secretion of β-amyloid enriched in the more toxic Aβ x-42 species. Notably, synthesis of the variant KCNIP4 isoform is also detrimental to brain physiology, as it results in the concomitant blockade of the fast kinetics of potassium channels. This alternative splicing shift is observed at high frequency in tissue samples from Alzheimer's disease patients, suggesting that RNA polymerase III cogenes may be upstream determinants of alternative splicing that significantly contribute to homeostasis and pathogenesis in the brain.
The Journal of Cell Biology 05/2011; 193(5):851-66. · 10.26 Impact Factor
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Sara Massone, Irene Vassallo,
Gloria Fiorino,
Manuele Castelnuovo,
Federica Barbieri,
Roberta Borghi,
Massimo Tabaton,
Mauro Robello,
Elena Gatta,
Claudio Russo,
Tullio Florio,
Giorgio Dieci,
Ranieri Cancedda,
Aldo Pagano
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ABSTRACT: Alternative splicing is a central component of human brain complexity; nonetheless, its regulatory mechanisms are still largely unclear. In this work, we describe a novel non-coding (nc) RNA (named 17A) RNA polymerase (pol) III-dependent embedded in the human G-protein-coupled receptor 51 gene (GPR51, GABA B2 receptor). The stable expression of 17A in SHSY5Y neuroblastoma cells induces the synthesis of an alternative splicing isoform that abolish GABA B2 intracellular signaling (i.e., inhibition of cAMP accumulation and activation of K(+) channels). Indeed, 17A is expressed in human brain, and we report that it is upregulated in cerebral tissues derived from Alzheimer disease patients. We demonstrate that 17A expression in neuroblastoma cells enhances the secretion of amyloid β peptide (Aβ) and the Aβ x-42/Αβ x-40 peptide ratio and that its synthesis is induced in response to inflammatory stimuli. These data correlate, for the first time, the activity of a novel pol III-dependent ncRNA to alternative splicing events and, possibly, to neurodegeneration induced by abnormal GABA B function. We anticipate that further analysis of pol III-dependent regulation of alternative splicing will disclose novel regulatory pathways associated to brain physiology and/or pathology.
Neurobiology of Disease 09/2010; 41(2):308-17. · 5.40 Impact Factor
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ABSTRACT: We recently described Rolly Protein (ROLP), a small protein synthesized by substrate-adherent cells in a broad range of tissues. In a first set of experiments performed taking advantage of bone forming tibial cartilage as an experimental model we showed that ROLP transcription is associated to cells in an active proliferation state, whereas its downregulation is observed when cell proliferation decreases. Taking advantage of siRNA technology we also documented the expression modulation of some apoptosis-related genes in ROLP-silenced cells. In this work we search for the possible molecular interactors of ROLP by using both the antibody array approach as well as the co-immunoprecipitation approach. Results suggest the occurrence of an interaction of ROLP with Erythrocyte membrane Protein Band 4.1/3 (Epb4.1/3), an oncosuppressor downregulated in tumor development and in metastatic tissues; in addition we report experimental results that keep in line also with a potential interaction of ROLP with other PDZ-containing proteins. We also present experimental evidences supporting a role played by ROLP in cell adhesion thus supporting the existence of a biologically relevant link between ROLP and Epb4.1/3. We here suggest that ROLP might exert its biological role cooperating with Epb4.1/3, a protein that is involved in biological pathways that are often inhibited in tumor metastasis. Given the role of Epb4.1/3 in contrasting cancerogenesis we think that its cooperation with ROLP might be relevant in cancer studies and deserves further investigation.
International Journal of Molecular Sciences 02/2009; 10(5):2054-65. · 2.60 Impact Factor
