Phospholipase C-related catalytically inactive protein enhances cisplatin-induced apoptotic cell death

Asano, Shigetaka; Maetani, Yuka; Ago, Yukio; Kanematsu, Takashi

doi:10.1016/j.ejphar.2022.175273

Cited by 1 publication

(1 citation statement)

References 38 publications

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“…The two products, IP3 and DAG, are important intracellular second messengers involved in Ca 2+ signaling regulation and protein kinase C signaling activation, respectively 9,10 . Hence, PLC orchestrates diverse cellular processes and behaviors, including cell growth, differentiation, migration, and cell death 11–14 . There are at least thirteen PLC isozymes grouped in 6 classes (β, δ, ε, γ, η, ζ) in mammals with similar enzymatic function, but each PLC has its own spectrum of activators, expression pattern, and subcellular distribution 15–17 .…”

Section: Introductionmentioning

confidence: 99%

De novovariants inPLCG1are associated with hearing impairment, ocular pathology, and cardiac defects

Ma,

Zheng,

et al. 2024

Preprint

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Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-trisphosphate and diacylglycerol, important signaling molecules involved in many cellular processes.PLCG1encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations ofPLCG1are observed in multiple cancers, but only one germline variant has been reported. Here we describe three unrelated individuals withde novoheterozygous missense variants inPLCG1(p.Asp1019Gly, p.His380Arg, and p.Asp1165Gly) who exhibit variable phenotypes including hearing loss, ocular pathology and cardiac septal defects. To model these variantsin vivo, we generated the analogous variants in theDrosophilaortholog,small wing(sl). We created a null alleleslT2Aand assessed the expression pattern.slis broadly expressed, including in wing discs, eye discs, and a subset of neurons and glia. Loss ofslcauses wing size reductions, ectopic wing veins and supernumerary photoreceptors. We document that mutant flies exhibit a reduced lifespan and age-dependent locomotor defects. Expressing wild-typeslinslT2Amutant rescues the loss-of-function phenotypes whereas expressing the variants causes lethality. Ubiquitous overexpression of the variants also reduces viability, suggesting that the variants are toxic. Ectopic expression of an established hyperactivePLCG1variant (p.Asp1165His) in the wing pouch causes severe wing phenotypes, resembling those observed with overexpression of the p.Asp1019Gly or p.Asp1165Gly variants, further arguing that these two are gain-of-function variants. However, the wing phenotypes associated with p.His380Arg overexpression are mild. Our data suggest that thePLCG1 de novoheterozygous missense variants are pathogenic and contribute to the features observed in the probands.

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