ARC
a protein expressed in brain, pancreatic islets, muscle capillaries and skeletal muscle sarcolemmas. Enriched in nuclei and mitochondria. Mitochondrial form is an apoptosis repressor that blocks multiple modes of cell death. Nuclear form may be involved in RNA splicing. 3 alternatively spliced human isoforms have been reported. Isoform 1, also known as Nop30, contains a SR-rich C-terminus that mediates nuclear localization. Interacts with 'spectrin beta chain, non-erythrocytic 4' (SPTBN4) in primary hippocampal neurons, where it is recruited to Tip60 in nuclear speckles, forming a tight trimeric complex localizing to perichromatin regions. Appears to induce acetylation of Tip60 H4K12. Thus it may be involved memory consolidation and the process of long-term memory. Isoform 2, also known as Myp, functions as an apoptosis repressor that blocks multiple modes of cell death. Inhibits extrinsic apoptotic pathways through two different ways. Firstly by interacting with FAS and FADD upon FAS activation blocking death-inducing signaling complex (DISC) assembly. Secondly by interacting with CASP8 in a mitochondria localization- and phosphorylation-dependent manner, limiting the amount of soluble CASP8 available for DISC-mediated activation. Inhibits intrinsic apoptotic pathway in response to a wide range of stresses, through its interaction with BAX resulting in BAX inactivation, preventing mitochondrial dysfunction and release of pro-apoptotic factors. Inhibits calcium-mediated cell death by functioning as a cytosolic calcium buffer, dissociating its interaction with CASP8 and maintaining calcium homeostasis. Negatively regulates oxidative stress-induced apoptosis by phosphorylation-dependent suppression of the mitochondria-mediated intrinsic pathway, by blocking CASP2 activation and BAX translocation. Negatively regulates hypoxia-induced apoptosis in part by inhibiting the release of cytochrome c from mitochondria in a caspase-independent manner. Also inhibits TNF-induced necrosis by preventing TNF-signaling pathway through TNFRSF1A interaction abrogating the recruitment of RIPK1 to complex I. Finally through its role as apoptosis repressor, promotes vascular remodeling through inhibition of apoptosis and stimulation of proliferation, in response to hypoxia. Inhibits too myoblast differentiation through caspase inhibition. Highly expressed in heart and skeletal muscle. Detected at low levels in placenta, liver, kidney and pancreas. Note: This description may include information from UniProtKB.
Molecular Function: calcium ion binding; caspase binding; cysteine-type endopeptidase inhibitor activity involved in apoptotic process; death effector domain binding; death receptor binding; identical protein binding; kinase binding; metal ion binding; phosphatase binding; protein binding; signaling receptor binding
Biological Process: blood vessel remodeling; cardiac muscle cell apoptotic process; cellular response to hypoxia; inhibition of cysteine-type endopeptidase activity; inhibition of cysteine-type endopeptidase activity involved in apoptotic process; intrinsic apoptotic signaling pathway; mRNA processing; mRNA splice site recognition; myoblast differentiation; negative regulation of apoptotic process; negative regulation of cardiac muscle cell apoptotic process; negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; negative regulation of cytosolic calcium ion concentration; negative regulation of death-inducing signaling complex assembly; negative regulation of extrinsic apoptotic signaling pathway; negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway; negative regulation of intrinsic apoptotic signaling pathway; negative regulation of mitochondrial calcium ion concentration; negative regulation of mitochondrial membrane permeability involved in apoptotic process; negative regulation of muscle atrophy; negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway; negative regulation of programmed necrotic cell death; negative regulation of protein targeting to mitochondrion; negative regulation of release of cytochrome c from mitochondria; negative regulation of striated muscle cell apoptotic process; negative regulation of tumor necrosis factor-mediated signaling pathway; protein complex oligomerization; regulation of apoptotic process; regulation of gene expression; regulation of NIK/NF-kappaB signaling; regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum; release of sequestered calcium ion into cytosol by sarcoplasmic reticulum; response to hypoxia; response to injury involved in regulation of muscle adaptation; response to ischemia; smooth muscle cell proliferation
