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• Marquina, Maribel; Ricart‐Fort, Montserrat; Díaz‐Parra, Rocío; Aviles, Sandra Lopez; Yance, Tula & Quirós, Pablo [Show all 10 contributors for this article] (2025). Biostimulants in plant brassinosteroid hormone receptor BRI1 activation—a new system to evaluate activation capacity. The FEBS Journal. ISSN 1742-464X. 293(3), p. 677–697. doi: 10.1111/febs.70235. Full text in Research Archive Show summary

  The search for innovative and alternative chemical methods to manage plant growth is an ever‐increasing reality. Biostimulants, products of biological origin, have shown promise in improving various agronomic characteristics and boosting yield. However, the selection and characterization of biostimulant matrices is a complex process that requires rigorous evaluation adapted to the specific needs of each plant. Because mixtures of biologically active compounds are present in biostimulants, efficient methods are required to characterize their potential mode of action. In this study, a new approach was developed to assess the biological activity of biostimulants by activating specific plant receptors involved in key physiological processes. It is based on the heterologous expression in fission yeast of brassinosteroid receptor protein Brassinosteroid Insensitive 1 (BRI1), which is involved in plant growth and development, and its specific activation by brassinolide (BL). The method involves the identification of highly expressed genes in response to BL activation of the BRI1 receptor, to generate a GFP reporter gene system that is switched on when biostimulants activate the BRI1 receptor. The biostimulants selected for testing were hydrolysates of animal origin. The results not only revealed variations in BRI1 activation among biostimulants, but also highlighted that samples from the same origin exhibit different BRI1 activation capacities depending on their processing methods. This new method enables direct classification of the mode of action of biostimulants by assessing their ability to activate specific plant receptors, providing a valuable resource for biostimulant research and development.

• Wang, Shixiong; Santacana-Font, Gemma; Kedra, Darek; Gilfillan, Siv; Tena-Chaves, David & Bergholtz, Helga [Show all 13 contributors for this article] (2025). The harmonized activities of HER2–HER3 heterodimer and deacetylated FOXA1 evade hormone response by regulating FOXA1 chromatin binding. Nucleic Acids Research (NAR). ISSN 0305-1048. 53(20). doi: 10.1093/nar/gkaf1086. Full text in Research Archive Show summary

  FOXA1 is a key transcription factor that mediates the effects of estrogen receptor (ER) and HER2 signaling in breast cancer. However, the mechanisms underlying FOXA1 regulation by HER2 and ER remain poorly understood. Here, we investigated FOXA1 regulation in cells with varying HER2 levels and its impact on endocrine therapy response. Chromatin interaction analyses revealed that high HER2 levels enhance FOXA1 binding to chromatin regions while reducing ER occupancy. Mechanistically, FOXA1 is acetylated by the histone acetyltransferase EP300 at the WD1 domain in ER-positive cells, attenuating its DNA binding at HER2-induced chromatin regions. Conversely, FOXA1 deacetylation—triggered by HER2/HER3 activation—increases its binding to ER-independent regions and promotes insensitivity to hormone therapy. In a luminal breast cancer patient-derived xenograft model, HER2/HER3 signaling increased FOXA1 chromatin binding and reduced sensitivity to ER-targeted treatment. We identify HDAC2 as a key deacetylase modulating FOXA1 acetylation and partially mediating the effects of HER2/HER3 signaling. Altogether, our findings highlight the significance of FOXA1 acetylation, regulated by the HER2/HER3–HDAC2–FOXA1 axis, in controlling FOXA1 chromatin binding and shaping breast cancer progression and therapy response. These insights may inform future therapeutic strategies.

• Chica-Balaguera, Nathalia; Portantier, Marina; Nyquist-Andersen, Mari; Burriel, Silvia Espada & Aviles, Sandra Lopez (2022). Uncoupling of Mitosis and Cytokinesis Upon a Prolonged Arrest in Metaphase Is Influenced by Protein Phosphatases and Mitotic Transcription in Fission Yeast. Frontiers in Cell and Developmental Biology. 10. doi: 10.3389/fcell.2022.876810. Full text in Research Archive Show summary

  Depletion of the Anaphase-Promoting Complex/Cyclosome (APC/C) activator Cdc20 arrests cells in metaphase with high levels of the mitotic cyclin (Cyclin B) and the Separase inhibitor Securin. In mammalian cells this arrest has been exploited for the treatment of cancer with drugs that engage the spindle assembly checkpoint and, recently, with chemical inhibitors of the APC/C. While most cells arrested in mitosis for prolonged periods undergo apoptosis, others skip cytokinesis and enter G1 with unsegregated chromosomes. This process, known as mitotic slippage, generates aneuploidy and increases genomic instability in the cancer cell. Here, we analyze the behavior of fission yeast cells arrested in mitosis through the transcriptional silencing of the Cdc20 homolog slp1 . While depletion of slp1 readily halts cells in metaphase, this arrest is only transient and a majority of cells eventually undergo cytokinesis and show steady mitotic dephosphorylation. Notably, this occurs in the absence of Cyclin B (Cdc13) degradation. We investigate the involvement of phosphatase activity in these events and demonstrate that PP2A-B55 Pab1 is required to prevent septation and, during the arrest, its CDK-mediated inhibition facilitates the induction of cytokinesis. In contrast, deletion of PP2A-B56 Par1 completely abrogates septation. We show that this effect is partly due to this mutant entering mitosis with reduced CDK activity. Interestingly, both PP2A-B55 Pab1 and PP2A-B56 Par1 , as well as Clp1 (the homolog of the budding yeast mitotic phosphatase Cdc14) are required for the dephosphorylation of mitotic substrates during the escape. Finally, we show that the mitotic transcriptional wave controlled by the RFX transcription factor Sak1 facilitates the induction of cytokinesis and also requires the activity of PP2A-B56 Par1 in a mechanism independent of CDK.

• Marquina, Maribel; Lambea, Eva; Carmona, Mercé; Sánchez-Marinas, Marta; Aviles, Sandra Lopez & Ayte, José [Show all 8 contributors for this article] (2022). A new negative feedback mechanism for MAPK pathway inactivation through Srk1 MAPKAP kinase. Scientific Reports. 12(1). doi: 10.1038/s41598-022-23970-8. Full text in Research Archive Show summary

  Abstract The fission yeast mitogen-activated kinase (MAPK) Sty1 is essential for cell survival in response to different environmental insults. In unstimulated cells, Sty1 forms an inactive ternary cytoplasmatic complex with the MAPKK Wis1 and the MAPKAP kinase Srk1. Wis1 phosphorylates and activates Sty1, inducing the nuclear translocation of the complex. Once in the nucleus, Sty1 phosphorylates and activates Srk1, which in turns inhibits Cdc25 and cell cycle progression, before being degraded in a proteasome-dependent manner. In parallel, active nuclear Sty1 activates the transcription factor Atf1, which results in the expression of stress response genes including pyp2 (a MAPK phosphatase) and srk1 . Despite its essentiality in response to stress, persistent activation of the MAPK pathway can be deleterious and induces cell death. Thus, timely pathway inactivation is essential to ensure an appropriate response and cell viability. Here, uncover a role for the MAPKAP kinase Srk1 as an essential component of a negative feedback loop regulating the Sty1 pathway through phosphorylation and inhibition of the Wis1 MAPKK. This feedback regulation by a downstream kinase in the pathway highlights an additional mechanism for fine-tuning of MAPK signaling. Thus, our results indicate that Srk1 not only facilitates the adaptation to stress conditions by preventing cell cycle progression, but also plays an instrumental role regulating the upstream kinases in the stress MAPK pathway.

• Stonyte, Vilte; Martîn, Ruth Martîn; Segura-Pena, Dario; Sekulic, Nikolina & Aviles, Sandra Lopez (2020). Requirement of PP2A-B56 Par1 for the Stabilization of the CDK Inhibitor Rum1 and Activation of APC/C Ste9 during Pre-Start G1 in S. pombe. iScience. 23(5). doi: 10.1016/j.isci.2020.101063. Full text in Research Archive Show summary

  Exit from the cell cycle during the establishment of quiescence and upon cell differentiation requires the sustained inactivation of CDK complexes. Fission yeast cells deprived of nitrogen halt cell cycle progression in pre-Start G1, before becoming quiescent or undergoing sexual differentiation. The CDK inhibitor Rum1 and the APC/C activator Ste9 are fundamental for this arrest, but both are down-regulated by CDK complexes. Here, we show that PP2A-B56Par1 is instrumental for Rum1 stabilization and Ste9 activation. In the absence of PP2A-B56Par1, cells fail to accumulate Rum1, and this results in persistent CDK activity, Ste9 inactivation, retention of the mitotic cyclin Cdc13, and impaired withdrawal from the cell cycle during nitrogen starvation. Importantly, mutation of a putative B56 interacting motif in Rum1 recapitulates these defects. These results underscore the relevance of CDK-counteracting phosphatases in cell differentiation, establishment of the quiescent state, and escape from it in cancer cells.

• Martîn, Ruth Martîn; Stonyte, Vilte & Aviles, Sandra Lopez (2020). Protein phosphatases in G1 regulation. International Journal of Molecular Sciences. ISSN 1661-6596. 21:395(2), p. 1–15. doi: 10.3390/ijms21020395. Full text in Research Archive Show summary

  Eukaryotic cells make the decision to proliferate, to differentiate or to cease dividing during G1, before passage through the restriction point or Start. Keeping cyclin-dependent kinase (CDK) activity low during this period restricts commitment to a new cell cycle and is essential to provide the adequate timeframe for the sensing of environmental signals. Here, we review the role of protein phosphatases in the modulation of CDK activity and as the counteracting force for CDK-dependent substrate phosphorylation, in budding and fission yeast. Moreover, we discuss recent findings that place protein phosphatases in the interface between nutritional signalling pathways and the cell cycle machinery.

• Wang, Shixiong; Singh, Sachin Kumar; Madhumohan, Katika; Lopez-Aviles, Sandra & Rodriguez, Antoni Hurtado (2018). High Throughput Chemical Screening Reveals Multiple Regulatory Proteins on FOXA1 in Breast Cancer Cell Lines. International Journal of Molecular Sciences. ISSN 1661-6596. 19(4123). doi: 10.3390/ijms19124123. Full text in Research Archive Show summary

  Forkhead box A1 (FOXA1) belongs to the forkhead class transcription factor family, playing pioneering function for hormone receptors in breast and prostate cancers, and mediating activation of linage specific enhancers. Interplay between FOXA1 and breast cancer specific signaling pathways has been reported previously, indicating a regulation network on FOXA1 in breast cancer cells. Here in this study, we aimed to identify which are the proteins that could potentially control FOXA1 function in breast cancer cell lines expressing different molecular markers. We first established a luciferase reporter system reflecting FOXA1 binding to DNA. Then, we applied high throughput chemical screening of multiple protein targets and mass spectrometry in breast cancer cell lines expressing different molecular markers: ER positive/HER2 negative (MCF-7), ER positive/HER2 positive (BT474), and ER negative/HER2 positive (MDA-MB-453). Regardless of estrogen receptor status, HER2 (human epidermal growth factor receptor 2) enriched cell lines showed similar response to kinase inhibitors, indicating the control of FOXA1 by cell signaling kinases. Among these kinases, we identified additional receptor tyrosine kinases and cyclin-dependent kinases as regulators of FOXA1. Furthermore, we performed proteomics experiments from FOXA1 inmunoprecipitated protein complex to identify that FOXA1 interacts with several proteins. Among all the targets, we identified cyclin-dependent kinase 1 (CDK1) as a positive factor to interact with FOXA1 in BT474 cell line. In silico analyses confirmed that cyclin-dependent kinases might be the kinases responsible for FOXA1 phosphorylation at the Forkhead domain and the transactivation domain. These results reveal that FOXA1 is potentially regulated by multiple kinases. The cell cycle control kinase CDK1 might control directly FOXA1 by phosphorylation and other kinases indirectly by means of regulating other proteins.

• Wang, Shixiong; Singh, Sachin Kumar; Katika, MR; Aviles, Sandra Lopez & Hurtado, Antoni (2018). High Throughput Chemical Screening Reveals Multiple Regulatory Proteins on FOXA1 in Breast Cancer Cell Lines. International Journal of Molecular Sciences. ISSN 1661-6596. 19(12). doi: 10.3390/ijms19124123. Full text in Research Archive
• Martîn, Ruth Martîn; Portantier, Marina; Chica-Balaguera, Nathalia; Nyquist-Andersen, Mari; Mata, J & Lopez-Aviles, Sandra (2017). A PP2A-B55-Mediated Crosstalk between TORC1 and TORC2 Regulates the Differentiation Response in Fission Yeast. Current Biology. ISSN 0960-9822. 27(2), p. 175–188. doi: 10.1016/j.cub.2016.11.037. Full text in Research Archive Show summary

  Extracellular cues regulate cell fate, and this is mainly achieved through the engagement of specific transcriptional programs. The TORC1 and TORC2 complexes mediate the integration of nutritional cues to cellular behavior, but their interplay is poorly understood. Here, we use fission yeast to investigate how phosphatase activity participates in this interplay during the switch from proliferation to sexual differentiation. We find that loss of PP2A-B55Pab1 enhances the expression of differentiation-specific genes and leads to premature conjugation. pab1 deletion brings about a transcriptional profile similar to TORC1 inactivation, and deletion of pab1 overcomes the repression of differentiation genes in cells overexpressing TORC1. Importantly, we show that this effect is mediated by an increased TORC2-AKT (Gad8) signaling. Under nutrient-rich conditions, PP2A-B55Pab1 dephosphorylates Gad8 Ser546, repressing its activity. Conversely, TORC1 inactivation upon starvation leads to the inactivation of PP2A-B55Pab1 through the Greatwall-Endosulfin pathway. This results in the activation of Gad8 and the commitment to differentiation. Thus, PP2A-B55Pab1 enables a crosstalk between the two TOR complexes that controls cell-fate decisions in response to nutrient availability.

• Martîn, Ruth Martîn & Lopez-Aviles, Sandra (2017). Express yourself: how PP2A-B55Pab1 helps TORC1 talk to TORC2. Current Genetics. ISSN 0172-8083. 64(1), p. 43–51. doi: 10.1007/s00294-017-0721-8. Full text in Research Archive
• Rothe, Christiane; Rødland, Gro Elise; Anda, Silje; Stonyte, Vilte; Boye, Erik & Lopez-Aviles, Sandra [Show all 7 contributors for this article] (2017). A checkpoint-independent mechanism delays entry into mitosis after UV irradiation. Journal of Cell Science. ISSN 0021-9533. 130(23), p. 4028–4037. doi: 10.1242/jcs.204693. Full text in Research Archive
• Gómez-Hierro, Alba; Lambea, Eva; Giménez-Zaragoza, David; Aviles, Sandra Lopez; Yance-Chávez, Tula & Montserrat, Marta [Show all 9 contributors for this article] (2015). Ssp1 CaMKK: A sensor of actin polarization that controls mitotic commitment through Srk1 in schizosaccharomyces pombe. PLOS ONE. 10(11). doi: 10.1371/journal.pone.0143037. Full text in Research Archive

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