We have studied cebnip3, the orthologue of bnip3 in C, elegans. Sequence analysis reveals that the different domains of bnip3 have been conserved throughout evolution. cebnip3 contains a C-terminal transmembrane (TM) ...
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We have studied cebnip3, the orthologue of bnip3 in C, elegans. Sequence analysis reveals that the different domains of bnip3 have been conserved throughout evolution. cebnip3 contains a C-terminal transmembrane (TM) domain, a conserved domain (CD) of 19 amino acids, a BCL-2 homology-3 (BH3)-like domain and a PEST sequence. cebnip3 is expressed primarily as a 25 kDa monomer and a 50 kDa homodimer, After transfection, cebnip3 protein is rapidly degraded through a ubiquitin-dependent pathway by the proteasome. Like bnip3, the TM domain of cebnip3 mediates the localization of the protein to mitochondria and is also necessary for homodimerization and cell death in mammalian cells. Neither the putative BH3 domain nor conserved domain is necessary for killing. cebnip3 protein interacts with CED-9 and BCL-X-L, but unlike other pro-apoptotic BCL-2 family members, the BH3-like domain does not participate in dimerization, The cebnip3 TM domain mediates interaction with both CED-9 and BCL-XL. cebnip3 interacts with CED-3 but co-expression of CED-3 and cebnip3 does not significantly enhance induction of cell death in the presence or absence of CED-4, cebnip3 kills mammalian cells by a caspase-independent mechanism. In conclusion, we find that although cebnip3 interacts with CED-9 and CED-3 it kills by a BH3- and caspase-independent mechanism.
Clonogenic survival and early cell death during treatment of human colon carcinoma cells were investigated following X-irradiation (IR) alone, IR followed by 5-FU for 24 h, and Taxol administered 24 h before TR and 5F...
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Clonogenic survival and early cell death during treatment of human colon carcinoma cells were investigated following X-irradiation (IR) alone, IR followed by 5-FU for 24 h, and Taxol administered 24 h before TR and 5F-U. The investigated cell lines were: HCT116, 40-16 clonally derived from HCT116, and two HCT116 variants: N6CHR3 expressing hMLH1, and TP53 null cells denoted HCT116 p53-/-. The objective was to determine efficacy of the combined treatment and to correlate response with constitutive levels of TP53, WAF1, and hMLH1 proteins, as well as with mRNA levels of the apoptosis-related genes survivin, bnip3, and MYC. At the end of treatment with 5-FU, the proportion of viable cells was between 0.65 and 0.70 for all cell lines. Additional cell loss occurred in 40-16 and HCT116 p53-/- cells following administration of Taxol before IR and 5-FU. Radiation sensitivity was unaffected by combined treatments, except for Taxol, irradiation, and 5-FU sequence in the HCT116 p53-/- and 40-16 cell lines, where radiation sensitivity determined by clonogenic survival curve slopes was doubled or quadrupled, respectively. Under our present experimental conditions, treatment response did not correlate with TP53 or hMLH1 status, but was associated with apoptosis-related genes, most notably bnip3, (C) 2000 Wiley-Liss, Inc.
The process of mitophagy, in which mitochondria are selectively turned over at the autophagolysosome, plays a central role in both eliminating dysfunctional mitochondria and reducing mitochondrial mass as an adaptive ...
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The process of mitophagy, in which mitochondria are selectively turned over at the autophagolysosome, plays a central role in both eliminating dysfunctional mitochondria and reducing mitochondrial mass as an adaptive response to key physiological stresses, such as hypoxia, nutrient deprivation, and DNA damage. Defects in mitophagy have been linked to altered mitochondrial metabolism, production of excess reactive oxygen species and ferroptosis, heightened inflammasome activation, altered cell fate decisions, and senescence, among other cellular consequences. Consequently, functional mitophagy contributes to proper tissue differentiation and repair and metabolic homeostasis, limiting inflammatory responses and modulating tumor progression and metastasis. This review examines the major pathways that control mitophagy, including PINK1-dependent mitophagy and bnip3/NIX-dependent mitophagy. It also discusses the cellular signaling mechanisms used to sense mitochondrial dysfunction to activate mitophagy and how defective mitophagy results in deregulated tumor cell growth and cancer.
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