The perilipin‐2 (adipophilin) coat of cytosolic lipid droplets is regulated by an Arf1‐dependent mechanism in HC11 mouse mammary epithelial cells

Pauloin, Alain; Adenot, Pierre; Hue-Beauvais, Catherine; Chanat, Éric

doi:10.1002/cbin.10547

Cited by 4 publications

(3 citation statements)

References 46 publications

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“…The Arf1 inhibitor Exo2 prevents the activation of certain Arf1-specific GEF enzymes by binding to their Sec7 domain [40]. This inhibition impedes the release of secretory vesicles from the endoplasmic reticulum (ER) to the Golgi apparatus [41,42], as well as reduces cellular lipid storage by inhibiting perilipin-2 expression [43]. Besides, this molecule presents high specificity for vesicle cargo since it impedes the retrograde transport of the Shiga toxin from the early endosomes to the ER, but does not hinder cholera toxin transport between the same compartments [42].…”

Section: Arf1 and Its Inhibitors In Cancer Therapymentioning

confidence: 99%

Drugging the Small GTPase Pathways in Cancer Treatment: Promises and Challenges

Prieto-Domínguez

Parnell

Teng

2019

Cells

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Small GTPases are a family of low molecular weight GTP-hydrolyzing enzymes that cycle between an inactive state when bound to GDP and an active state when associated to GTP. Small GTPases regulate key cellular processes (e.g., cell differentiation, proliferation, and motility) as well as subcellular events (e.g., vesicle trafficking), making them key participants in a great array of pathophysiological processes. Indeed, the dysfunction and deregulation of certain small GTPases, such as the members of the Ras and Arf subfamilies, have been related with the promotion and progression of cancer. Therefore, the development of inhibitors that target dysfunctional small GTPases could represent a potential therapeutic strategy for cancer treatment. This review covers the basic biochemical mechanisms and the diverse functions of small GTPases in cancer. We also discuss the strategies and challenges of inhibiting the activity of these enzymes and delve into new approaches that offer opportunities to target them in cancer therapy.

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Section: Arf1 and Its Inhibitors In Cancer Therapymentioning

confidence: 99%

Drugging the Small GTPase Pathways in Cancer Treatment: Promises and Challenges

Prieto-Domínguez

Parnell

Teng

2019

Cells

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“…An attractive candidate is RalF, which acts as an Arf1 guanine nucleotide exchange factor (GEF), thus activating the small GTPase Arf1 on LCVs ( Nagai et al, 2002 ). Activated, GTP-bound Arf1 regulates through perilipin-2 the phospholipid monolayer that stabilizes LDs and controls the cellular availability of neutral lipids for metabolic purposes ( Pauloin et al, 2016 ). Moreover, upon activation, Arf1 and the coat complex COPI form LD-ER membrane bridges for targeting catabolic enzymes ( Wilfling et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

The large GTPase Sey1/atlastin mediates lipid droplet- and FadL-dependent intracellular fatty acid metabolism of Legionella pneumophila

Hüsler

Stauffer

Keller

et al. 2023

eLife

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The amoeba-resistant bacterium Legionella pneumophila causes Legionnaires' disease and employs a type IV secretion system (T4SS) to replicate in the unique, ER-associated Legionella-containing vacuole (LCV). The large fusion GTPase Sey1/atlastin is implicated in ER dynamics, ER-derived lipid droplet (LD) formation, and LCV maturation. Here we employ cryo-electron tomography, confocal microscopy, proteomics, and isotopologue profiling to analyze LCV-LDs interactions in the genetically tractable amoeba Dictyostelium discoideum. Dually fluorescence-labeled D. discoideum producing LCV and LD markers revealed that Sey1 as well as the L. pneumophila T4SS and the Ran GTPase activator LegG1 promote LCV-LDs interactions. In vitro reconstitution using purified LCVs and LDs from parental or Dsey1 mutant D. discoideum indicated that Sey1 and GTP promote this process. Sey1 and the L. pneumophila fatty acid transporter FadL are implicated in palmitate catabolism and palmitate-dependent intracellular growth. Taken together, our results reveal that Sey1 and LegG1 mediate LD- and FadL-dependent fatty acid metabolism of intracellular L. pneumophila.

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“…During lactation, a significant amount of cytoplasmic lipid droplets (CLDs) is accumulated in mammary epithelial cells [33]. Earlier studies have explored lipid droplet formation in HC11 cells to study the role of genes that involve in this process [34]. Therefore, we next performed lipid droplet formation by oil red staining assay.…”

Section: Mir-148a Regulates Milk Protein Synthesis By Controlling Hpi...mentioning

confidence: 99%

Hematopoietic PBX‐interacting protein is a novel regulator of mammary epithelial cell differentiation

et al. 2021

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Hematopoietic PBX‐interacting protein (HPIP, also known as PBXIP1) is an estrogen receptor (ER) interacting protein that regulates estrogen‐mediated breast cancer cell proliferation and tumorigenesis. However, its functional significance in the context of mammary gland development is unexplored. Here, we report that HPIP is required for prolactin (PRL)‐induced lactogenic differentiation in vitro. Molecular analysis of HPIP expression in mice revealed its induced expression at pregnancy and lactation stages of mammary gland. Moreover, PRL is a lactogenic hormone that controls pregnancy as well as lactation and induces Hpip/Pbxip1 expression in a signal transducer and activator of transcription 5a‐dependent manner. Using mammary epithelial and lactogenic‐competent cell lines, we further show that HPIP plays a regulatory role in PRL‐mediated mammary epithelial cell differentiation, which is measured by acini formation, β‐casein synthesis, and lipid droplet formation. Further mechanistic studies using pharmacological inhibitors revealed that HPIP modulates PRL‐induced β‐casein synthesis via phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) activation. This study also identified HPIP as a critical regulator of autocrine PRL signaling as treatment with the PRL receptor antagonist Δ1‐9‐G129R‐hPRL restrained HPIP‐mediated PRL synthesis, AKT activation, and β‐casein synthesis in cultured HC11 cells. Interestingly, we also uncovered that microRNA‐148a (miR‐148a) antagonizes HPIP‐mediated mammary epithelial cell differentiation. Together, our study identified HPIP as a critical regulator of PRL signaling and revealed a novel molecular circuitry involving PRL, HPIP, PI3K/AKT, and miR‐148a that controls mammary epithelial cell differentiation in vitro.

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The perilipin‐2 (adipophilin) coat of cytosolic lipid droplets is regulated by an Arf1‐dependent mechanism in HC11 mouse mammary epithelial cells

Cited by 4 publications

References 46 publications

Drugging the Small GTPase Pathways in Cancer Treatment: Promises and Challenges

Drugging the Small GTPase Pathways in Cancer Treatment: Promises and Challenges

The large GTPase Sey1/atlastin mediates lipid droplet- and FadL-dependent intracellular fatty acid metabolism of Legionella pneumophila

Hematopoietic PBX‐interacting protein is a novel regulator of mammary epithelial cell differentiation

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