To Prime, or Not to Prime: That Is the Question

Potter, Danielle S.; Letaï, Anthony

doi:10.1101/sqb.2016.81.030841

Cited by 50 publications

(49 citation statements)

References 77 publications

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“…In our cartilage explant system, navitoclax showed consistent and robust elimination of the p16 tdTom ‐positive chondrocyte population with a single treatment for 3 d. The observation that the fluorescence intensity of the p16 tdTom ‐negative fraction was unchanged, combined with the initiation of cleaved caspase‐3 after navitoclax treatment, suggests that down‐regulation of p16 Ink4a expression was not responsible but that selective apoptosis was the primary mechanism for this result. Because of the complex regulation of apoptosis by the Bcl‐2 family of proteins, experimental approaches such as BH3 profiling (57) may be required to determine the precise mechanisms by which p16‐high chondrocytes are preferentially targeted for cell death upon navitoclax treatment.…”

Section: Discussionmentioning

confidence: 99%

Controlled induction and targeted elimination of p16^INK4a‐expressing chondrocytes in cartilage explant culture

Sessions¹,

Copp

Liu

et al. 2019

The FASEB Journal

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Cellular senescence is a phenotypic state that contributes to age‐related diseases through the secretion of matrix‐degrading and inflammatory molecules. An emerging therapeutic strategy for osteoarthritis (OA) is to selectively eliminate senescent cells by initiating apoptosis. This study establishes a cartilage explant model of senescence induction and senolytic clearance using p16Ink4a expression as a biomarker of senescence. Growth‐factor stimulation of explants increased the expression of p16Ink4a at both the mRNA and protein levels. Applying this culture system to cartilage from p16tdTom reporter mice (a knockin allele with tdTomato fluorescent protein regulated by the endogenous p16Ink4a promoter) demonstrated the emergence of a p16‐high population that was quantified using flow cytometry for tdTomato. Cell sorting was used to separate chondrocytes based on tdTomato fluorescence and p16‐high cells showed higher senescence‐associated β‐galactosidase activity and increased gene expression of the senescence‐associated secretory phenotype as compared with p16‐low cells. The potential for effective senolysis within the cartilage extracellular matrix was assessed using navitoclax (ABT‐263). Navitoclax treatment reduced the percentage of p16‐high cells from 17.9 to 6.1% (mean of 13 matched pairs; P < 0.001) and increased cleaved caspase‐3 confirmed apoptotic activity. Together, these findings establish a physiologically relevant cartilage explant model for testing the induction and elimination of senescent chondrocytes, which will support investigations of senolytic therapy for OA.—Sessions, G. A., Copp, M. E., Liu, J.‐Y., Sinkler, M. A., D'Costa, S., Diekman, B. O. Controlled induction and targeted elimination of p16INK4a‐expressing chondrocytes in cartilage explant culture. FASEB J. 33, 12364–12373 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Controlled induction and targeted elimination of p16^INK4a‐expressing chondrocytes in cartilage explant culture

Sessions¹,

Copp

Liu

et al. 2019

The FASEB Journal

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“…Using luciferase reporter assays and ChIP analysis, it was shown that c‐Myc directly binds to the FLIP promoter to effect this change . A recent paper from the Letai lab proposed that highly proliferative tissues with high c‐Myc activity (as is found in many cancers) are apoptotically primed; in this regard, c‐Myc‐mediated repression of FLIP expression may contribute to this apoptotic priming . In conclusion, FLIP is regulated by multiple, interconnected pathways providing potential opportunities for indirect modulation of FLIP by agents targeting the relevant pathways in specific tissues/cancers ( see below ).…”

Section: Flip Regulationmentioning

confidence: 99%

FLIP as a therapeutic target in cancer

2018

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One of the classic hallmarks of cancer is disruption of cell death signalling. Inhibition of cell death promotes tumour growth and metastasis, causes resistance to chemo‐ and radiotherapies as well as targeted agents, and is frequently due to overexpression of antiapoptotic proteins rather than loss of pro‐apoptotic effectors. FLIP is a major apoptosis‐regulatory protein frequently overexpressed in solid and haematological cancers, in which its high expression is often correlated with poor prognosis. FLIP, which is expressed as long (FLIP(L)) and short (FLIP(S)) splice forms, achieves its cell death regulatory functions by binding to FADD, a critical adaptor protein which links FLIP to the apical caspase in the extrinsic apoptotic pathway, caspase‐8, in a number of cell death regulating complexes, such as the death‐inducing signalling complexes (DISCs) formed by death receptors. FLIP also plays a key role (together with caspase‐8) in regulating another form of cell death termed programmed necrosis or ‘necroptosis’, as well as in other key cellular processes that impact cell survival, including autophagy. In addition, FLIP impacts activation of the intrinsic mitochondrial‐mediated apoptotic pathway by regulating caspase‐8‐mediated activation of the pro‐apoptotic Bcl‐2 family member Bid. It has been demonstrated that FLIP can not only inhibit death receptor‐mediated apoptosis, but also cell death induced by a range of clinically relevant chemotherapeutic and targeted agents as well as ionizing radiation. More recently, key roles for FLIP in promoting the survival of immunosuppressive tumour‐promoting immune cells have been discovered. Thus, FLIP is of significant interest as an anticancer therapeutic target. In this article, we review FLIP's biology and potential ways of targeting this important tumour and immune cell death regulator.

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“…Currently, BH3-profiling is the technique used to assay the state of apoptotic 752 priming for different tissue types, however, this technique requires the addition of BH3 753 peptides at high concentrations, and can only be performed on cells/tissues after 754 permeabilization of the plasma membrane (Potter and Letai 2016). As an alternative, we 755…”

mentioning

confidence: 99%

The carboxyl-terminal sequence of Bim enables Bax activation and killing of unprimed cells

Chi

Nguyen

Pemberton

et al. 2019

Preprint

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31The Bcl-2 family BH3 protein Bim promotes apoptosis at mitochondria by 32 activating the pore forming proteins Bax and Bak and by inhibiting the anti-apoptotic 33proteins Bcl-XL, Bcl-2 and Mcl-1. Bim binds to these proteins via its BH3 domain and to 34 the mitochondrial membrane by a carboxyl-terminal sequence (CTS). In cells killed by 35Bim, the expression of a Bim mutant in which the CTS was deleted (BimL-dCTS) 36triggered variable amounts of apoptosis that correlated with inhibition of anti-apoptotic 37proteins being sufficient to permeabilize mitochondria isolated from the same cells. 38Detailed analysis of the molecular mechanism demonstrated that BimL-dCTS inhibited 39Bcl-XL but did not activate Bax. Our examination of additional point mutants 40unexpectedly revealed that the CTS of Bim is required for physiological concentrations 41of Bim to activate Bax and that different residues in the CTS enable Bax activation and 42 binding to membranes. 43

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To Prime, or Not to Prime: That Is the Question

Cited by 50 publications

References 77 publications

Controlled induction and targeted elimination of p16^INK4a‐expressing chondrocytes in cartilage explant culture

Controlled induction and targeted elimination of p16^INK4a‐expressing chondrocytes in cartilage explant culture

FLIP as a therapeutic target in cancer

The carboxyl-terminal sequence of Bim enables Bax activation and killing of unprimed cells

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