Protein kinase C controls activation of the DNA integrity checkpoint

Soriano-Carot, María; Quilis, Inma; Bañó, M. Carmen; Igual, J. Carlos

doi:10.1093/nar/gku373

Cited by 23 publications

(27 citation statements)

References 71 publications

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“…In S . cerevisiae , Pkc1 controls multiple cellular processes in addition to the downstream MAP kinase cascade, including activation of DNA integrity checkpoints [42], microtubule functions [43], glycerol metabolism [44, 45], as well as organization of the actin cytoskeleton [46]. In C .…”

Section: Discussionmentioning

confidence: 99%

Signaling through Lrg1, Rho1 and Pkc1 Governs Candida albicans Morphogenesis in Response to Diverse Cues

et al. 2016

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The capacity to transition between distinct morphological forms is a key virulence trait for diverse fungal pathogens. A poignant example of a leading opportunistic fungal pathogen of humans for which an environmentally responsive developmental program underpins virulence is Candida albicans. C. albicans mutants that are defective in the transition between yeast and filamentous forms typically have reduced virulence. Although many positive regulators of C. albicans filamentation have been defined, there are fewer negative regulators that have been implicated in repression of filamentation in the absence of inducing cues. To discover novel negative regulators of filamentation, we screened a collection of 1,248 C. albicans homozygous transposon insertion mutants to identify those that were filamentous in the absence of inducing cues. We identified the Rho1 GAP Lrg1, which represses filamentous growth by stimulating Rho1 GTPase activity and converting Rho1 to its inactive, GDP-bound form. Deletion of LRG1 or introduction of a RHO1 mutation that locks Rho1 in constitutively active, GTP-bound state, leads to filamentation in the absence of inducing cues. Deletion of the Rho1 downstream effector PKC1 results in defective filamentation in response to diverse host-relevant inducing cues, including serum. We further established that Pkc1 is not required to sense filament-inducing cues, but its kinase activity is critical for the initiation of filamentous growth. Our genetic analyses revealed that Pkc1 regulates filamentation independent of the canonical MAP kinase cascade. Further, although Ras1 activation is not impaired in a pkc1Δ/pkc1Δ mutant, adenylyl cyclase activity is reduced, consistent with a model in which Pkc1 functions in parallel with Ras1 in regulating Cyr1 activation. Thus, our findings delineate a signaling pathway comprised of Lrg1, Rho1 and Pkc1 with a core role in C. albicans morphogenesis, and illuminate functional relationships that govern activation of a central transducer of signals that control environmental response and virulence programs.

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Section: Discussionmentioning

confidence: 99%

Signaling through Lrg1, Rho1 and Pkc1 Governs Candida albicans Morphogenesis in Response to Diverse Cues

et al. 2016

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“…Indeed, this proposed role for PKCδ fits well with the evidence that PKCδ functions as an apical regulator of apoptosis. Some studies place PKCδ upstream of the DNA damage sensors, DNA-dependent protein kinase, and ataxia telangiectasia mutated (ATM) and suggest a role for PKCδ in their activation in response to DNA damage (Bharti et al, 1998; Arango et al, 2012; Soriano-Carot, Quilis, Bano, & Igual, 2014). PKCδ has also been shown to function downstream of ATM activation (Li et al, 2004; LaGory, Sitailo, & Denning, 2010).…”

Section: Biological Functions Of Pkcδmentioning

confidence: 99%

“…In this regard, PKCδ-dependent regulation of MAPK pathways (Efimova, Broome, & Eckert, 2004; Murriel et al, 2004; Blank et al, 2013), PI3K-Akt (Murriel et al, 2004), signal transducer and activator of transcription-1 (STAT-1) (DeVries, Kalkofen, Matassa, & Reyland, 2004), and NFκB (Ren et al, 2014; Dong et al, 2015) has been shown in many contexts. In a second scenario, PKCδ could directly regulate the DNA damage response and cell cycle arrest mechanisms, as discussed above, pushing a cell toward initiation of apoptotic pathways (Bharti et al, 1998; Yoshida et al, 2003; LaGory et al, 2010; Arango et al, 2012; Soriano-Carot et al, 2014). Evidence supports both scenarios, raising the possibility that PKCδ, or a PKCδ effector, may have a dual function in cell survival and cell death.…”

Section: Biological Functions Of Pkcδmentioning

confidence: 99%

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Reyland

Jones

2016

Pharmacology & Therapeutics

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The serine–threonine protein kinase, protein kinase C-δ (PKCδ), is emerging as a bi-functional regulator of cell death and proliferation. Studies in PKCδ−/− mice have confirmed a pro-apoptotic role for this kinase in response to DNA damage and a tumor promoter role in some oncogenic contexts. In non-transformed cells, inhibition of PKCδ suppresses the release of cytochrome c and caspase activation, indicating a function upstream of apoptotic pathways. Data from PKCδ−/− mice demonstrate a role for PKCδ in the execution of DNA damage-induced and physiologic apoptosis. This has led to the important finding that inhibitors of PKCδ can be used therapeutically to reduce irradiation and chemotherapy-induced toxicity. By contrast, PKCδ is a tumor promoter in mouse models of mammary gland and lung cancer, and increased PKCδ expression is a negative prognostic indicator in Her2+ and other subtypes of human breast cancer. Understanding how these distinct functions of PKCδ are regulated is critical for the design of therapeutics to target this pathway. This review will discuss what is currently known about biological roles of PKCδ and prospects for targeting PKCδ in human disease.

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“…Thus, linking these protein targets to brain developmental effects induced by BafA1 or Rapa seems plausible. Other proteins, like BMPs, TNC, PKC, and CST3 could potentially and indirectly aid either of the two drugs in having impacts on the cellular processes shown in Figure 3a by their roles in astrocytic maturation and mitogenesis, migration, tumor invasion, and controlling DNA checkpoints required for maintaining genomic integrity [45,[47][48][49].…”

Section: Implications Of Bafa1/rapa-dysregulated Intracellular Astrocmentioning

confidence: 99%

Autophagy Modulators Profoundly Alter the Astrocyte Cellular Proteome

Sher

Gao

Coombs

2020

Cells

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Autophagy is a key cellular process that involves constituent degradation and recycling during cellular development and homeostasis. Autophagy also plays key roles in antimicrobial host defense and numerous pathogenic organisms have developed strategies to take advantage of and/or modulate cellular autophagy. Several pharmacologic compounds, such as BafilomycinA1, an autophagy inducer, and Rapamycin, an autophagy inhibitor, have been used to modulate autophagy, and their effects upon notable autophagy markers, such as LC3 protein lipidation and Sequestosome-1/p62 alterations are well defined. We sought to understand whether such autophagy modulators have a more global effect upon host cells and used a recently developed aptamer-based proteomic platform (SOMAscan®) to examine 1305 U-251 astrocytic cell proteins after the cells were treated with each compound. These analyses, and complementary cytokine array analyses of culture supernatants after drug treatment, revealed substantial perturbations in the U-251 astrocyte cellular proteome. Several proteins, including cathepsins, which have a role in autophagy, were differentially dysregulated by the two drugs as might be expected. Many proteins, not previously known to be involved in autophagy, were significantly dysregulated by the compounds, and several, including lactadherin and granulins, were up-regulated by both drugs. These data indicate that these two compounds, routinely used to help dissect cellular autophagy, have much more profound effects upon cellular proteins.

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Protein kinase C controls activation of the DNA integrity checkpoint

Cited by 23 publications

References 71 publications

Signaling through Lrg1, Rho1 and Pkc1 Governs Candida albicans Morphogenesis in Response to Diverse Cues

Signaling through Lrg1, Rho1 and Pkc1 Governs Candida albicans Morphogenesis in Response to Diverse Cues

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Autophagy Modulators Profoundly Alter the Astrocyte Cellular Proteome

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