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FLASH GENE

Symbol

BNIP3

contributors: mct/pgu - updated : 15-06-2015

HGNC name	BCL2/adenovirus E1B 19kDa interacting protein 3
HGNC id	1084

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       moderately Endocrine pancreas         Lymphoid/Immune lymph node       highly Nervous nerve cranial nerve     highly Reproductive male system prostate     highly Respiratory lung       highly Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     highly Connective bone     highly

cells

System Cell Pubmed Species Stage Rna symbol Endocrine islet cell (alpha,beta...) Lymphoid/Immune macrophage

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES		Hydrophobic
STRUCTURE

motifs/domains	a BCL-2 homology domain
	a C terminal putative membrane-spanning hydrophobic domain, transmembrane domain that is essential for homodimerization and proapoptotic function

mono polymer

homomer , heteromer , dimer

HOMOLOGY

interspecies

homolog to rattus Bnip3 (94.1pc)

Homologene

FAMILY

NIP3 family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria,outer
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,nucleus,nucleoplasm
	intracellular,nuclear envelope
text	coexpression with the E1B/19 kda protein results in a shift in BNIP3 localization pattern to the nuclear envelope
	is localized to the nucleus in the majority of glioblastoma multiforme (GBM) tumors and fails to induce cell death
	localized to both mitochondria and the endoplasmic reticulum (ER)
	localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics

basic FUNCTION	apoptosis inducing protein, even in the presence of BCL2
	playing a role in hypoxia-induced cell death in epithelial cells that could be circumvented by growth factor signaling
	mediates mitochondrial dysfunction through activation of BAX or BAK1 which is independent of mitochondrial permeability transition pore opening
	might play a role in gastric carcinoma development
	implicated in the pathogenesis of cancer and heart disease
	involved in the induction of autophagy and required for mitophagy (specialized autophagy that targets mitochondria) , and is clearly a survival mechanism that promotes tumor progression
	in tumor cells, BNIP3 is regulated by hypoxia and deregulation is associated with tumor growth
	transcriptional repression function causing reduced apoptosis-inducing factor expression and increased resistance to apoptosis in GBM tumors
	mediates permeabilization of mitochondria and release of cytochrome c via a novel mechanism
	BNIP3 and PDK1 are involved in two important pathways, cell death and glycolytic, playing critical roles in these pathways in cardiomyocytes after severe hypoxia
	might have a dual function in the myocardium, where it regulates both mitochondrial turnover via autophagy and cell death and that these are two separate processes activated by BNIP3
	contributes to cell death through activation of the mitochondrial pathway of apoptosis
	caused an increase in mitochondrial protease activity, suggesting that BNIP3 might promote degradation of proteins in the mitochondria
	BNIP3-mediated impairment of mitochondrial respiration induces mitochondrial turnover by activating mitochondrial autophagy
	key regulator of cell death/autophagy and can act as an effector of a necrosis-like, atypical death program
	regulates the apoptotic balance as an autophagy receptor that induces removal of both mitochondria and ER
	role in limiting mitochondrial mass and maintaining mitochondrial integrity in the liver that has consequences for lipid metabolism and disease
	BNIP3 and AIFM1 cooperate to induce apoptosis and cavitation during epithelial morphogenesis
	could play a protective role in tumor cells under hypoxia
	BNIP3 regulates mitophagy during hypoxia, whereas BNIP3L is required for mitophagy during development of the erythroid lineage
	temporally regulated role for BNIP3 and BNIP3L in the generation of robust NK cell memory

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	binding adenovirus E1B, BCL2, bhrf1 of Epstein-Barr virus
	interacting with BCL2L1 (critically regulates the apoptosis of terminally differentiated chondrocytes)
	interacting with BNIP3L
	interacting with FOXO3 (FOXO3 controls the transcription of autophagy-related genes, including MAP1LC3 and BNIP3
	direct transcriptional target of E2F1 that is necessary and sufficient for E2F1-induced cell death
	interacts with OPA1, leading to mitochondrial fragmentation and apoptosis
	under hypoxic conditions VEGFA counteracts and masks the apoptosis promoting affects of BNIP3
	regulatory target of HRAS
	induction of autophagy in response to BNIP3 is a protective response activated by the cell that involves DNM1L-mediated mitochondrial fission and recruitment of Parkin
	BNIP3 and AIFM1 cooperate to induce apoptosis and cavitation during epithelial morphogenesis
	partners of CLN8 are VAPA, C14orf1/hERG28, STX8, GABARAPL2, BNIP3 and BNIP3L proteins and are associated with biologically relevant processes such as synthesis and transport of lipids, vesicular/membrane trafficking, autophagy/mitophagy and apoptosis
	different mitophagy effectors, including the mitophagy receptors BNIP3L, BNIP3 and FUNDC1 and the PINK1/Parkin pathway, have been identified to participate in the selective clearance of mitochondria

cell & other

REGULATION

activated by

E2F1 (E2F1 activates BNIP3 and the intrinsic death pathway in ventricular myocytes)

induced by	dramatically by hypoxia and by overexpression of HIF1A (role during hypoxia induced cell death)
		nitric oxide that causes cell death in macrophages

repressed by	TYMP
		TP53 (TP53 suppressed BNIP3 expression by directly binding to the TP53-response element motif and recruiting corepressor SIN3A to the BNIP3 promoter)

Other	in heart muscle, regulated by hypoxia and Galphaq-dependent signaling , expression is associated with decreased of myocardial function
	under nonapoptotic conditions, NFKappaB transcriptionally silences BNIP3 gene transcription
	autophagic degradation of BNIP3 was dependent on ATG7 and MAP1LC3

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   by aberrant DNA methylation of the 5' CpG island and histone deacetylation in haematopoietic tumours tumoral     --low   in chronic pancreatitis and pancreatic cancer with poorer survival tumoral     --low   downregulated in primary myelofibrosis constitutional     --over   in heart failure and contributes to loss of myocardial cells during I/R (ischaemia/reperfusion) constitutional     --low   was protective against hypoxia-induced autophagy and cell death

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neurology neurodegenerative   . FOXO3 and BNIP3 as potential therapeutic targets in muscle wasting disorders and other degenerative and neoplastic diseases in which autophagy is involved cancer     . FOXO3 and BNIP3 as potential therapeutic targets in muscle wasting disorders and other degenerative and neoplastic diseases in which autophagy is involved cancer     treatment with Torin1, an MTOR inhibitor, decreased the BNIP3 level and enhanced the death of hypoxic tumor cells

ANIMAL & CELL MODELS