Diurnal pattern of rat pancreatic acinar cell replication

Biederbick, Annette; Elsässer, Hans-P.

doi:10.1007/s004410050997

Cited by 44 publications

(40 citation statements)

References 14 publications

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“…Staining of cells with the acidophilic lysosomal probe LysoTracker Red (LTR) revealed that HCQ caused an increase in lysosomal volume. Concomitantly, HCQ triggered an increase in the frequency of cytoplasmic organelles staining with monodansylcadaverine, a dye that specifically stains autophagic vacuoles (Biederbick et al, 1995;Munafo and Colombo, 2001) (Figure 1b). These effects were suppressed when cells were pretreated with Baf A 1 .…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine

et al. 2003

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Hydroxychloroquine (HCQ) is a lysosomotropic amine with cytotoxic properties. Here, we show that HCQ induces signs of lysosomal membrane permeabilization (LMP), such as the decrease in the lysosomal pH gradient and the release of cathepsin B from the lysosomal lumen, followed by signs of apoptosis including caspase activation, phosphatidylserine exposure, and chromatin condensation with DNA loss. HCQ also induces mitochondrial membrane permeabilization (MMP), as indicated by the insertion of Bax into mitochondrial membranes, the conformational activation of Bax within mitochondria, the release of cytochrome c from mitochondria, and the loss of the mitochondrial transmembrane potential. To determine the molecular order among these events, we introduced inhibitors of LMP (bafilomycin A 1 ), MMP (Bcl-X L , wild-type Bcl-2, mitochondrion-targeted Bcl-2, or viral mitochondrial inhibitor of apoptosis from cytomegalovirus), and caspases (Z-VAD.fmk) into the system. Our data indicate that caspase-independent MMP is rate-limiting for LMP-mediated caspase activation. Mouse embryonic fibroblasts lacking the expression of both Bax and Bak are resistant against hydroxychloroquine-induced apoptosis. Such Bax À/À Bak À/À cells manifest normal LMP, yet fail to undergo MMP and subsequent cell death. The data reported herein indicate that LMP does not suffice to trigger caspase activation and that Bax/Bak-dependent MMP is a critical step of LMP-induced cell death.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine

et al. 2003

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“…3). We used both inhibitors as recent reports have shown that lactacystin also inhibits cathepsin A activity of the lysosome and thus may not be proteasome-specific (27,28). Addition of these drugs did not cause increased cell death or overt aggregate formation.…”

Section: ␣-Synuclein Is Degraded By the Proteasome In Our Cellmentioning

confidence: 99%

α-Synuclein Is Degraded by Both Autophagy and the Proteasome

Webb

Ravikumar

Atkins

et al. 2003

Journal of Biological Chemistry

1,328

1,075

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Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of aggregates (Lewy bodies) in neurons. ␣-Synuclein is the major protein in Lewy bodies and rare mutations in ␣-synuclein cause early-onset PD. Consequently, ␣-synuclein is implicated in the pathogenesis of PD. Here, we have investigated the degradation pathways of ␣-synuclein, using a stable inducible PC12 cell model, where the expression of exogenous human wild-type, A30P, or A53T ␣-synuclein can be switched on and off. We have used a panel of inhibitors/ stimulators of autophagy and proteasome function and followed ␣-synuclein degradation in these cells. We found that not only is ␣-synuclein degraded by the proteasome, but it is also degraded by autophagy. A role for autophagy was further supported by the presence of ␣-synuclein in organelles with the ultrastructural features of autophagic vesicles. Since rapamycin, a stimulator of autophagy, increased clearance of ␣-synuclein, it merits consideration as a potential therapeutic for Parkinsons disease, as it is designed for chronic use in humans.

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“…Intracellular MDC was measured by fluorescence photometry (excitation at 380 nm and emission at 525 nm) (37). Autophagy was measured by the increase in fluorescence intensity of MDC-stained autophagosomes.…”

Section: Measurement Of Reactive Oxygen Intermediate (Roi)-mentioning

confidence: 99%