Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The epidermis is a stratified squamous epithelium in which keratinocytes progressively undergo terminal differentiation towards the skin surface leading to programmed cell death. In this respect we studied the role of caspases. Here, we show that caspase-14 synthesis in the skin is restricted to differentiating keratinocytes and that caspase-14 processing is associated with terminal epidermal differentiation. The pro-apoptotic executioner caspases-3, -6, and -7 are not activated during epidermal differentiation. Caspase-14 does not participate in apoptotic pathways elicited by treatment of differentiated keratinocytes with various death-inducing stimuli, in contrast to caspase-3. In addition, we show that non-cornifying oral keratinocyte epithelium does not express caspase-14 and that the parakeratotic regions of psoriatic skin lesions contain very low levels of caspase-14 as compared to normal stratum corneum. These observations strongly suggest that caspase-14 is involved in the keratinocyte terminal differentiation program leading to normal skin cornification, while the executioner caspases are not implicated. Cell Death and Differentiation (2000) 7, 1218 - 1224
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PMID:Epidermal differentiation does not involve the pro-apoptotic executioner caspases, but is associated with caspase-14 induction and processing. 1117 59

Apoptosis and necrosis in brain account for neurological sequelae in survivors of bacterial meningitis. In meningitis, several mechanisms may trigger death pathways leading to activation of transcription factors regulating caspases mRNA synthesis. Therefore, we used a multiprobe RNA protection assay (RPA) to examine the expression of 9 caspase-mRNA in the course of experimental Streptococcus pneumoniae meningitis in mouse brain. Caspase-6, -7 and -11 mRNA were elevated 6 hours after infection. 12 hours after infection caspases-1, -2, -8 and -12 mRNA rose. Caspase-14 mRNA was elevated 18 h and caspase-3 mRNA 24 h after infection. In situ hybridization detected caspases-3, -8, -11 and -12 mRNA in neurons of the hippocampal formation and neocortex. Development of sepsis was paralleled by increased transcription of caspases mRNA in the spleen. In TNFalpha-deficient mice all caspases examined were less upregulated, in TNF-receptor 1/2 knockout mice caspases-1, -2, -7, -11 and -14 mRNA were increased compared to infected control animals. In caspase-1 deficient mice, caspases-11, and -12 mRNA levels did not rise in meningitis indicating the necessity of caspase-1 activating these caspases. Hippocampal formations of newborn mice incubated with heat-inactivated S. pneumoniae R6 showed upregulation of caspase-1, -3, -11 and -12 mRNA. These observations suggest a tightly regulated caspases network at the transcriptional level in addition to the known cascade at the protein level.
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PMID:Transcriptional regulation of caspases in experimental pneumococcal meningitis. 1141 71

Caspase-14 is the only member of the caspase family that shows a restricted tissue expression. It is mainly confined to epidermal keratinocytes and in contrast to other caspases, is not activated during apoptosis induced by ultraviolet irradiation or cytotoxic substances. As it is cleaved under conditions leading to terminal differentiation of keratinocytes we suggested that caspase-14 plays a part in the physiologic cell death of keratinocytes leading to skin barrier formation. Here we show that retinoic acid, at concentrations inhibiting terminal differentiation of keratinocytes, strongly suppressed caspase-14 mRNA and protein expression by keratinocytes in monolayer culture and in a three-dimensional in vitro model of differentiating human epidermis (skin equivalent). By contrast, the expression of the caspases 3 and 8, which are both activated during conventional apoptosis, was increased and unchanged, respectively, after retinoic acid treatment. In addition to inhibition of differentiation in skin equivalents, retinoic acid treatment led to keratinocyte apoptosis and activation of caspase-3, both of which were undetectable in differentiated control skin equivalents. As this occurred in the absence of detectable caspase-14, our data demonstrate that caspase-14 is dispensable for keratinocyte apoptosis. The fact that in contrast to caspase-3 and caspase-8, caspase-14, similarly to other keratinocyte differentiation-associated proteins, is downregulated by retinoids, strongly suggests that this caspase, but not caspase-3 and -8, plays a part in terminal keratinocyte differentiation and skin barrier formation.
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PMID:Caspase-14 expression by epidermal keratinocytes is regulated by retinoids in a differentiation-associated manner. 1244 5

Whether terminal differentiation/stratum corneum formation of keratinocytes (KCs) represents a form of programmed cell death, utilizing mediators of classical apoptosis, is unclear. Apoptosis, an evolutionarily conserved death process, is comprised of extrinsic and intrinsic pathways, which converge using caspase 3. To define upstream and downstream caspases involved in terminal differentiation, we utilized human epidermal equivalents (EEs). Using submerged cultures comprised of human KCs, EEs were sequentially analyzed before and after being raised to an air/liquid (A/L) interface at 3-24 h intervals. At each time point, EEs were analyzed morphologically and for specific enzyme activity to distinguish different initiator (caspases 1, 2, 8, 9) and effector caspases (3, 6, 7). Terminal differentiation began at 6-8 h, as defined by stratum corneum with loricirin expression and completed at 18-24 h producing an epidermis resembling normal skin. Enzyme activity for caspases 1, 2, 3, 6, 7, 8, and 9 (but not 4, 5) was enhanced (>two-fold nmol/mg/h) at 3-6 h compared with submerged cultures. Processing of caspase 14 occurred at 18 h, and cleaved caspase 14 was increased at 24 h. Activated caspase 3-positive and terminal deoxynucleotidyl transferase-mediated nick end labeling-positive KCs were identified in EEs at 3-6 h corresponding to initiation sites of terminal differentiation. Addition of caspase inhibitors reduced levels of involucrin and loricrin in EEs raised to an A/L interface. We conclude caspases function as important death effectors strategically positioned at intersection of intrinsic and extrinsic pathways in KCs undergoing stratum corneum formation.
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PMID:Defining the caspase-containing apoptotic machinery contributing to cornification in human epidermal equivalents. 1636 27

Caspase-14, a cysteine endoproteinase belonging to the conserved family of aspartate-specific proteinases, was shown to play an important role in the terminal differentiation of keratinocytes and barrier function of the skin. In the present study, we developed a biofunctional compound that we described as a modulator of caspase-14 expression. Using normal human keratinocytes (NHK) in culture and human skin biopsies, this compound was shown to increase caspase-14 expression and partially reverse the effect of caspase-14-specific siRNA on NHK. Moreover, the increase in filaggrin expression visualized on skin biopsies and the recovery of the barrier structure after tape-stripping indicated that this compound could exhibit a beneficial effect on the skin barrier function. Considering the possible link between caspase-14 and the barrier function, a UVB irradiation on NHK and skin biopsies previously treated with the caspase-14 inducer, was performed. Results indicated that pretreated skin biopsies exhibited less signs of UV damage such as active caspase-3 and cyclobutane pyrimidine dimers (CPDs). Likewise, pretreated NHK were protected from UV-induced genomic DNA damage, as revealed by the Comet Assay. Finally, a clinical test showed a reduction of transepidermal water loss (TEWL) on the treated skin compared with placebo, under UV stress condition, confirming a protecting effect. Taken together, these results strongly suggest that, by increasing caspase-14 expression, the biofunctional compound could exhibit a protective effect on the skin barrier function, especially in case of barrier damage and UV irradiation.
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PMID:Skin presenting a higher level of caspase-14 is better protected from UVB irradiation according to in vitro and in vivo studies. 2267 75