Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BNIP3 and NIX are proteins related to the BH3-only family, which induce both cell death and autophagy. Consistent with their ability to induce cell death, BNIP3 and NIX are implicated in the pathogenesis of cancer and heart disease. In tumor cells, BNIP3 and NIX are regulated by hypoxia, and the deregulation of BNIP3 or NIX expression is associated with tumor growth. In heart muscle, BNIP3 and NIX are regulated by hypoxia and Galphaq-dependent signaling, respectively, and their expression is associated with decreased myocardial function. Apart from their role in cell death, BNIP3 and NIX are also implicated in the induction of autophagy. In erythroid cells, NIX is required for a specialized type of autophagy that targets mitochondria for elimination (mitophagy). Similarly, BNIP3 regulates mitophagy in response to hypoxia. In this review, we will discuss possible mechanisms by which BNIP3 and NIX induce cell death and mitophagy. We will also consider the potential relationship between cell death pathways and autophagy in development and homeostasis.
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PMID:Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. 1922 44

The BNIP3 subfamily of BH3-only proteins consists of BNIP3 and BNIP3-like (BNIP3L) proteins. These proteins form stable homodimerization complexes that localize to the outer membrane of the mitochondria after cellular stress. This promotes either apoptotic or non-apoptotic cell death such as autophagic cell death. Although the mammalian cells contain both members of this subfamily, the genome of Caenorhabditis elegans codes for a single BNIP3 ortholog, ceBNIP3, which shares homology in the transmembrane (TM) domain and in a conserved region close to the BH3 domain of mammalian BNIP3 protein. The cell death activities of BNIP3 and BNIP3L are determined by either the BH3 domain or the C-terminal TM domain. The TM domain of BNIP3 is unique, as it is capable of autonomous stable dimerization and contributes to mitochondrial localization of BNIP3. In knockout mouse models, BNIP3L was shown to be essential for normal erythrocyte differentiation and hematopoietic homeostasis, whereas BNIP3 plays a role in cellular responses to ischemia/reperfusion injury in the heart. Both BNIP3 and BNIP3L play a role in cellular responses to stress. Under hypoxia, both BNIP3 and BNIP3L expression levels are elevated and contribute to hypoxia-induced cell death. In addition, these proteins play critical roles in disease states. In heart disease, both BNIP3 and BNIP3L play a critical role in cardiomyocyte cell death following ischemic and non-ischemic injuries. In cancer, expression of BNIP3 and BNIP3L is downregulated by promoter hypermethylation or by homozygous deletion of the gene locus in certain cancers, whereas their expression was increased in other cancers. In addition, BNIP3 expression has been correlated with poor prognosis in some cancers. The results reviewed here suggest that BNIP3 and BNIP3L may be novel therapeutic targets for intervention because of their pathological roles in regulating cell death in disease states.
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PMID:BNIP3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions. 1964 97

B-cell leukemia/lymphoma 2 (BCL-2)/adenovirus E1B interacting protein 3 (BNIP3) and Nip-like protein X (NIX) are atypical BCL-2 homology domain 3-only proteins involved in cell death, autophagy, and programmed mitochondrial clearance. BNIP3 and NIX cause cell death by targeting mitochondria, directly through BCL-2-associated X protein- or BCL-2-antagonist/killer-dependent mechanisms, or indirectly through an effect on calcium stores in the endoplasmic reticulum. BNIP3 and NIX also induce autophagy through an effect on mitochondrial reactive oxygen species production, or by releasing Beclin 1 from inhibitory interactions with antiapoptotic BCL-2 family proteins. BNIP3 downregulates mitochondrial mass in hypoxic cells, whereas NIX is required for mitochondrial elimination during erythroid development. BNIP3 and NIX have an emerging role in human health. Cell death mediated by BNIP3 and NIX is implicated in heart disease and ischemic injury. Cancer progression is linked to loss of the prodeath function of BNIP3, but also to induction of its prosurvival activity. Finally, BNIP3 and NIX are implicated in mitochondrial quality control, which is important in aging and degenerative disease. Elucidation of the mechanisms by which BNIP3 and NIX regulate cell death, autophagy, and mitochondrial clearance may lead to treatments for these conditions.
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PMID:Mechanisms and biology of B-cell leukemia/lymphoma 2/adenovirus E1B interacting protein 3 and Nip-like protein X. 2112 15