Biology subjects

Fajas, L.

Publications and source records attributed to Fajas, L..

7 recordsLinked to original sources

bioRxiv2026

Inhibition of p107 alleviates liver steatosis by reducing de novo fatty acid synthesis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive hepatic lipid accumulation driven by increased de novo lipogenesis (DNL) and impaired lipid oxidation. p107, a member of the retinoblastoma (Rb) family, extensively studied in the context of cell cycle regulation and adipocyte differentiation recently has been identified as a metabolic regulator controlling thermogenic activity. However, its role in hepatic lipid homeostasis remains poorly understood. Here, we identify the cell cycle regulator p107 as a key modulator of hepatic lipid metabolism. p107 expression is increased in patients with MASLD and correlates with disease severity. In mouse models, global and liver-specific p107 deficiency protect against high-fat diet-induced steatosis without affecting body weight. This is associated with reduced expression of lipogenic enzymes including fatty acid synthase (FASN), and enhanced mitochondrial oxidative pathways. Conversely, hepatic restoration of p107 reversed these effects and promoted lipid accumulation and endoplasmic reticulum stress. Consistent with this in human hepatocytes, p107 silencing reduces lipid accumulation, decreases DNL and enhances mitochondrial respiration, whereas p107 overexpression induces the opposite phenotype. Notably, FASN knockdown attenuates the pro-steatotic effects of p107, indicating that it is a critical downstream mediator of p107. Together, these findings establish p107 as a physiological regulator of hepatic lipid metabolism, with its dysregulation contributing to the development of MASLD.

physiology↗

bioRxiv2025

CDK4 Restricts Triple-Negative Breast Cancer Cell Migration via Phosphorylation-Driven Activation of Myo9b RhoGAP Function

Cyclin-Dependent Kinase 4 (CDK4) is a key regulator of cell cycle progression, driving the G0/G1-to-S phase transition through phosphorylation of Retinoblastoma 1 (RB1). Clinically, CDK4/6 inhibitors are under investigation in Triple Negative Breast Cancer (TNBC), a subtype characterized by invasiveness, aggressiveness and poor prognosis. While CDK4 is primarily targeted for its role in proliferation, emerging evidence suggests it may also regulate other cellular processes. In particular, the mechanisms by which CDK4 could influence cancer cell migration, remain largely unexplored, particularly in highly heterogenous cell line like MDA-MB-231. This study investigates whether CDK4 contributes to the regulation of TNBC cells migration and identifies the pathways involved in MDA-MB-231 cells, independently of its role in proliferation. We demonstrate that loss or inhibition of CDK4, using respectively CRISPR/Cas9 mediated CDK4 knockout and pharmacological CDK4/6 inhibitor, leads to enhanced migration capacities and reorganization of actin subcellular networks. Mechanistically, the absence of CDK4 results in decreased phosphorylation of Myo9b at serine 1935 (S1935), which enhances RhoA signaling, a key driver of cytoskeletal dynamics, leading to polarity defects and increased cell migration. These findings reveal a non-canonical function of CDK4 in limiting TNBC cell migration through the CDK4/CyclinD-Myo9b-RhoA signaling axis. This work highlights the broader cellular roles of CDK4 beyond its established function in proliferation and suggest that inhibition of Myo9b-RhoA pathway could reduce metastatic behaviour in TNBC treated with CDK4/6i, thereby informing future co-therapeutic strategies against aggressive cancer subtypes.

cell biology↗

bioRxiv2024

CDK4 inactivation balances resistance to apoptosis with heightened metabolic sensitivity in triple negative breast cancer cells

The shift in the energetic demands of proliferating cells during tumorigenesis requires intense crosstalk between the cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism in normal tissues. However, in the context of cancer, where CDK4 is upregulated or stabilized, the metabolic role of CDK4 is barely understood. Using both genetic and pharmacological approaches, we aimed to determine the metabolic role of CDK4 in TNBC cells. Unexpectedly, deletion of CDK4 only slightly reduced triple-negative breast cancer (TNBC) cell proliferation and allowed tumor formation in vivo. Furthermore, proapoptotic stimuli failed to induce appropriate cell death in TNBC cells with CDK4 depletion or long-term CDK4/6 inhibitor treatment. Mechanistically, CDK4 enhances mitochondria-ER contact (MERC) formation, thus promoting mitochondrial fission and ER-mitochondrial calcium signaling. Phosphoproteomic analysis also revealed a role for CDK4 in regulating PKA activity at MERCs to sustain ER-mitochondrial calcium signaling. This proper CDK4-mediated mitochondrial calcium signaling is then required for metabolic flexibility of TNBC cells. Taken together, these results demonstrate that CDK4 inhibition leads to cell death resistance, inhibiting mitochondrial apoptosis and functions through attenuated MERCs formation and ER-mitochondrial calcium signaling in TNBC. Overall, this study provides new insights into the mechanisms of TNBC resistance to CDK4/6i therapy and paves the way to explore potential synergistic therapeutic targeting MERCs-associated metabolic shifts. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/613455v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@36f496org.highwire.dtl.DTLVardef@1f3aa1dorg.highwire.dtl.DTLVardef@258d49org.highwire.dtl.DTLVardef@15ed9a6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Hepatic lipid overload potentiates biliary epithelial cell activation via E2Fs

During severe or chronic hepatic injury, biliary epithelial cells (BECs), also known as cholangiocytes, undergo rapid reprogramming and proliferation, a process known as ductular reaction (DR), and allow liver regeneration by differentiating into both functional cholangiocytes and hepatocytes. While DR is a hallmark of chronic liver diseases, including advanced stages of non-alcoholic fatty liver disease (NAFLD), the early events underlying BEC activation are largely unknown. Here, we demonstrate that BECs readily accumulate lipids upon fatty acid (FA) treatment in BEC-derived organoids, and during high-fat diet feeding in mice. Lipid overload induces a metabolic rewiring to support the conversion of adult cholangiocytes into active BECs. Mechanistically, we found that lipid overload unleashes the activation of the E2F transcription factors in BECs, which drives cell cycle progression while promoting glycolytic metabolism. These findings demonstrate that fat overload is sufficient to initiate a DR, without epithelial damage, and provide new insights into the mechanistic basis of BEC activation, revealing unexpected connections between lipid metabolism, stemness, and regeneration.

cell biology↗

bioRxiv2022

CDK4 deletion in mice prevents fat accumulation and increases endurance capacity through activation of estrogen related receptor (ERR)driven oxidative metabolism in skeletal muscle

Cyclin-dependent kinase 4 (CDK4) canonical role is to control cell cycle progression from G1 to S phases. However, recent studies reported that CDK4 regulates energy metabolism in non-proliferating cells such as hepatocytes or adipocytes. The objective of our work is to study CDK4 function in skeletal muscle using a model of mice lacking CDK4 (cdk4-/-). By coupling treadmill running to indirect calorimetry, we show that cdk4-/- mice display improved endurance and higher capacity to use fat as fuel during exercise. Isolated muscles lacking CDK4 are more resistant to fatigue in response to repeated contractions and have increased oxidative capacity and mitochondrial content compared to cdk4+/+ muscles. Transcriptomic analysis reveals upregulation of genes controlled by the nuclear receptors estrogen-related receptors (ERRs) in cdk4-/- skeletal muscle, associated with elevated levels of the ERR co-activator PGC1a. Supporting in vivo results, C2C12 myotubes treated with a CDK4 inhibitor have increased mitochondrial oxygen consumption, PGC1 expression and ERR transcriptional activity measured by a luciferase reporter. In normal housing conditions, cdk4-/- mice show an increased basal metabolic rate and are resistant to weight gain and fat accumulation. In conclusion, our study uncovers a role for CDK4 in the control of skeletal muscle metabolism. Moreover, CDK4 inhibition may be an alternative strategy against obesity-associated metabolic disorders.

physiology↗

bioRxiv2020

Pancreatic β-cell specific loss of E2f1 impairs insulin secretion and β-cell identity through the epigenetic repression of non β-cell programs

The loss of pancreatic {beta}-cell identity emerges as an important feature of type 2 diabetes development, but the molecular mechanisms are still elusive. Here, we explore the cell-autonomous role of the cell cycle regulator and transcription factor E2F1 in the maintenance of {beta}-cell identity and insulin secretion. We show that the {beta}-cell-specific loss of E2f1 function in mice triggers glucose intolerance associated with defective insulin secretion, an altered -to-{beta}-cell ratio, a downregulation of many {beta}-cell genes and a concomitant increase of non-{beta}-cell markers. Mechanistically, the epigenomic profiling of non-beta cell upregulated gene promoters identified an enrichment of bivalent H3K4me3/H3K27me3 or H3K27me3 marks. Conversely, downregulated genes were enriched in active chromatin H3K4me3 and H3K27ac histone marks. We find that histone deacetylase inhibitors modulate E2F1 transcriptional and epigenomic signatures associated with these {beta}-cell dysfunctions. Finally, the pharmacological inhibition of E2F transcriptional activity in human islets also impairs insulin secretion and the expression of {beta}-cell identity genes. Our data suggest that E2F1 is critical for maintaining {beta}-cell identity through a sustained repression of non {beta}-cell transcriptional programs.

physiology↗

bioRxiv2019

PamgeneAnalyzeR open and reproducible pipeline for kinase profiling

Protein phosphorylation - catalyzed by protein kinases - is the most common post-translational modification. It increases the functional diversity of the proteome and influences various aspects of normal physiology and can be altered in disease states. High throughput profiling of kinases is becoming an essential experimental approach to investigate their activity and this can be achieved using technologies such as PamChip(R) arrays provided by PamGene for kinase activity measurement. Here we present \"pamgeneAnalyzeR\", an R package developed as an alternative to the manual steps necessary to extract the data from PamChip(R) peptide microarrays images in a reproducible and robust manner. The extracted data can be directly used for downstream analysis.\n\nAvailability and implementationPamgeneAnalyzeR is implemented in R and can be obtained from https://github.com/amelbek/pamgeneAnalyzeR.

bioinformatics↗