Biology subjects

Potiri, M.

Publications and source records attributed to Potiri, M..

3 recordsLinked to original sources

bioRxiv2025

RpS12-mediated induction of the Xrp1short isoform links ribosomal protein mutations to cell competition

Cell competition, a universal yet enigmatic phenomenon, eliminates less-fit cells via interactions with their neighbors. It was originally described in Drosophila mosaics, where heterozygous ribosomal protein (Rp+/-) mutant cells are eliminated by wild-type neighbors. The transcription factor Xrp1 mediates most of the Rp+/- -associated phenotypes, including reduced competitiveness and translation. Although RpS12 is required for Xrp1 induction in Rp+/- cells, the mechanism remained unresolved. We demonstrate that RpS12, via alternative splicing, induces the Xrp1 short (Xrp1short) isoform expression in Rp+/- cells, which is both necessary and sufficient for their elimination. Strikingly, RpS12 overexpression in wild-type cells is sufficient to induce Xrp1short expression and confer a "loser" phenotype. While Xrp1long isoform is not required in Rp+/- cells, expression of either Xrp1 isoform is sufficient to promote the loser status in wild-type cells. We further identify Syncrip, an RNA-binding protein reduced in Rp+/- cells, as a critical Xrp1 suppressor; its depletion in wild-type cells activates Xrp1-dependent competition. Our findings establish RpS12s specialized function in Xrp1short promotion, not proteotoxic stress, as the primary driver in Rp+/- cells, providing new perspectives that challenge and refine prevailing models. Our work contributes in long-standing questions about ribosomal protein-linked fitness surveillance and provides insights into ribosomopathy pathologies.

developmental biology↗

bioRxiv2024

A neural alternative splicing program controls cellular function and growth in Pancreatic Neuroendocrine tumours

Pancreatic neuroendocrine tumours (PanNETs) are a rare heterogeneous group of neoplasms that arise from pancreatic islet cells. The hormone secreting function of pancreatic neuroendocrine cells is altered in PanNETs, rendering these tumours functional or non-- functional (secreting excessive or lower levels of hormones, respectively). Genome wide approaches have revealed the genomic landscape of PanNETs but have not shed light on this problematic hormone secretion. In the present work, we show that alternative splicing (AS) deregulation is responsible for changes in the secretory ability of PanNET cells. We reveal a group of alternative microexons that are regulated by the RNA binding protein SRRM3 and are preferentially included in mRNAs in PanNET cells, where SRRM3 is also upregulated. These microexons are part of a larger neural program regulated by SRRM3. We show that their inclusion gives rise to protein isoforms that change stimulus-induced secretory vesicles and their trafficking in PanNET cells. Moreover, the increased inclusion of these microexons results in an enhanced neuronal component in PanNET tumours. Using knock-down and splicing switching oligonucleotides in cellular and animal PanNET models, we show that decrease of the SRRM3 levels or even of the inclusion levels of the three most deregulated microexons can significantly alter the PanNET cell characteristics. Collectively, our study links secretory impairment and nerve dependency to alternative splicing deregulation in PanNETs, providing promising therapeutic targets for PanNET treatment.

cancer biology↗

bioRxiv2020

Nuclear IQGAP1 promotes gastric cancer cell growth by altering the splicing of a cell-cycle regulon in co-operation with hnRNPM

In response to oncogenic signals, Alternative Splicing (AS) regulators such as SR and hnRNP proteins show altered expression levels, subnuclear distribution and/or post-translational modification status, but the link between signals and these changes remains unknown. Here, we report that a cytosolic scaffold protein, IQGAP1, performs this task in response to heat-induced signals. We show that in gastric cancer cells, a nuclear pool of IQGAP1 acts as a tethering module for a group of spliceosome components, including hnRNPM, a splicing factor critical for the response of the spliceosome to heat-shock. IQGAP1 controls hnRNPMs sumoylation, subnuclear localization and the relevant response of the AS machinery to heat-induced stress. Genome-wide analyses reveal that IQGAP1 and hnRNPM co-regulate the AS of a cell cycle-related RNA regulon in gastric cancer cells, thus favouring the accelerated proliferation phenotype of gastric cancer cells. Overall, we reveal a missing link between stress signals and AS regulation.

molecular biology↗