Biology subjects

Ruiz-Losada, M.

Publications and source records attributed to Ruiz-Losada, M..

3 recordsLinked to original sources

bioRxiv2025

Dpp and Immune Response Pathways Factors Mediate Paracrine Induction of Senescent Cells in Drosophila

Transition toward senescence is a cellular response to different stressors like ionizing radiation, telomere shortening or oncogene activation. This phenomenon is evolutionarily conserved across species, from insects to humans. Senescent cells (SCs) permanently withdraw from the cell cycle and undergo a series of physiological changes, most notably the acquisition of a robust secretory activity characterized by the release of numerous molecules, including cytokines, chemokines, and metalloproteinases. Through this program, termed Senescence-Associated Secretory Phenotype (SASP), SCs actively communicate with and influence their microenvironment. In mammalian tissues the number of SCs increases with age and their accumulation has been proposed to contribute to several age-associated pathologies. Studies in vertebrate systems have demonstrated that new SCs can arise through paracrine signaling from pre-existing SCs, a process that requires the activity of Transforming Growth Factor {beta} (TGF-{beta}). We have investigated the phenomenon of paracrine recruitment of SCs in the Drosophila wing disc. Our results show that an initial stress event induces a primary wave of SCs, comprising approximately 10% of the target cell population. Subsequently, a second wave of SCs emerges through paracrine signaling from the initial cohort, increasing the overall proportion of SCs to about 24%. The formation of this second wave is mediated by the growth factor Decapentaplegic (Dpp), the Drosophila ortholog of TGF-{beta}. Dpp activates a non-canonical signaling route in non-SCs, driving their conversion to a senescent state. This novel branch of the Dpp pathway engages several components of the innate immune response. Collectively, these findings underscore the evolutionary conservation of senescence-associated signaling networks and suggest that paracrine amplification of senescence may play a role in tumorigenesis and age-related diseases.

cell biology↗

bioRxiv2024

A function of Spalt proteins in heterochromatin organization and maintenance of genomic DNA integrity

The phylogenetically conserved Spalt proteins regulate gene expression and participate in a variety of cell fate choices during multicellular development, generally acting as transcriptional repressors in different gene regulatory networks. Paradoxically, besides their roles as DNA sequence-specific transcription factors, Spalt proteins show a consistent localization to heterochromatic regions. They can act through interactions with the Nucleosome remodeling and deacetylase complex (NuRD) to promote closing of open chromatin domains, but their activities as epigenetic regulators also rely on interactions with DNA Methyltransferases or with the Lysine-specific histone demethylase LSD1, suggesting that they can participate in multiple regulatory mechanisms. Here we describe several major consequences of loss of spalt function in Drosophila cells, including changes in chromatin accessibility affecting mostly pericentromeric heterochromatin, the generation of DNA damage, alterations in the localization of chromosomes within the nucleus in polyploid cells of the salivary glands and miss-expression of transposable elements. We suggest that most of these effects are related to roles of Spalt proteins in the regulation of heterochromatin formation. We propose that Drosophila Spalt proteins have two complementary functions, acting as sequence-specific transcriptional repressors on specific target genes and regulating more global gene silencing through the generation or maintenance of heterochromatic domains.

developmental biology↗

bioRxiv2021

p53 pro-apoptotic activity is regulated by the G2/M promoting factor Cdk1 in response to DNA damage

Exposure to genotoxic stress promotes cell-cycle arrest and DNA repair or apoptosis. These "life" or "death" cell fate decisions often rely on the activity of the tumor suppressor gene p53. Therefore, how p53 activity is precisely regulated is essential to maintain tissue homeostasis and to prevent cancer development. Here we demonstrate that Drosophila p53 pro-apoptotic activity is regulated by the G2/M kinase Cdk1. We find that cell cycle arrested or endocycle-induced cells are refractory to ionizing radiation induced apoptosis. We show that the p53 protein is not able to bind to and to activate the expression of the pro-apoptotic genes in experimentally arrested cells. Our results indicate that p53 genetically and physically interacts with Cdk1 and that p53 pro-apoptotic role is regulated by the cell cycle status of the cell. We propose a model in which cell cycle progression and p53 pro-apoptotic activity are molecularly connected to coordinate the appropriate response after DNA damage.

developmental biology↗