SM-20 Is a Novel Mitochondrial Protein That Causes Caspase-dependent Cell Death in Nerve Growth Factor-dependent Neurons

Lipscomb, Elizabeth A.; Sarmiere, Patrick D.; Freeman, Robert S.

doi:10.1074/jbc.m008407200

Cited by 91 publications

(88 citation statements)

References 26 publications

(29 reference statements)

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“…Interestingly, the C-terminal fragment of Falkor, which we isolated from MEFs resistant to cisplatin-induced growth arrest has the greatest homology to SM-20, while the N-terminal fractions of the two proteins share little similarity with each other (see Figure 2b). Additionally, SM-20 was shown to contain a mitochondrial localization domain at its N-terminus, which is not conserved in Falkor (Lipscomb et al, 2001). The finding by Foca et al (2000) reporting increased expression of a cDNA closely related to SM-20 in endometrial carcinomas further supports an important role in growth control for SM-20 and its homologs.…”

Section: Discussionsupporting

confidence: 54%

“…On the one hand, SM-20 was identified as a growth factor responsive gene in rat smooth muscle cells (Wax et al, 1994). On the other hand, it was also reported to be a p53 target gene in rat fibroblasts (Madden et al, 1996) and a mitochondrial apoptosis related gene in sympathetic neurons (Lipscomb et al, 1999(Lipscomb et al, , 2001. These seemingly contradicting reports may suggest that like other cell growth regulators, SM-20 has a distinct regulatory role in different cell types and under different conditions.…”

Section: Discussionmentioning

confidence: 74%

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Falkor, a novel cell growth regulator isolated by a functional genetic screen

et al. 2002

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A novel cell growth regulator, named Falkor, was identified using a functional approach to mammalian gene cloning, the Genetic Supressor Elements (GSE) method. In this screen, expression of the C-terminal domain of Falkor conferred cells with resistance to cisplatin-induced growth arrest. Expression of the Cterminus of Falkor, but not of the full-length protein, enhanced cell growth both following genotoxic stress and under normal conditions suggesting a general role for this protein in cell growth control. This effect of the Cterminus fragment was abrogated by over-expression of the full-length Falkor, suggesting that the fragment counteracts the function of the full-length protein. Falkor is encoded by a 2-kb mRNA which is present at different levels in various tissues, and is localized in the nucleus of cells. The C-terminal domain of Falkor, isolated from the GSE library, has significant homology to a known human and rat cell growth regulator, SM-20, and to the C. elegans protein EGL-9, recently shown to modify the Hypoxia Inducible Factor-1a. The homology suggests that these proteins share a functional domain that is conserved among a family of growth regulation proteins.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 74%

Falkor, a novel cell growth regulator isolated by a functional genetic screen

et al. 2002

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“…The identity of the enzyme(s) present in our light mitochondrial kidney fractions is not known. However, it is of interest to note that SM-20 contains a mitochondrial targeting sequence (22) and that the newly described PHD-4 isoform is highly expressed in kidney tissues and associates to light microsomes (21).…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A Prevents the Hypoxic Adaptation by Activating Hypoxia-inducible Factor-1α Pro-564 Hydroxylation

D’Angelo¹,

Duplan²,

Vigne

et al. 2003

Journal of Biological Chemistry

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Cells respond to low oxygen tensions by up-regulating the expression of genes involved in angiogenesis (e.g. vascular endothelial growth factor), erythropoiesis (e.g. erythropoietin), and glycolysis. The transcriptional activation of target genes is induced by a common transcription factor, hypoxia-inducible factor-1 (HIF-1). 1 HIF-1 was first identified as a heterodimeric transactivator that recognizes a specific DNA sequence, termed hypoxia-responsive element (HRE) in the 3Ј-untranslated region of the erythropoietin gene (1). HIF-1 consists of two subunits, HIF-1␣ and the aryl hydrocarbon receptor nuclear translocator, both of which belong to the large family of basic helixloop-helix-per-arnt-sim transcription factors (2, 3). Under normoxic conditions, HIF-1␣ subunits are unstable, being rapidly targeted to the ubiquitin-proteasome pathway. Degradation is mediated by a ubiquitin-protein isopeptide ligase (E3) complex, in which the von Hippel-Lindau protein (vHL) binds to a specific hydroxylated proline residue (Pro-564) within the oxygen-dependent degradation (ODD) domain of HIF-1␣ (4, 5). A major action of hypoxia is to suppress prolyl hydroxylation and degradation of HIF-1␣ by the proteasome. As a consequence, the protein accumulates, migrates to the nucleus, and associates with the aryl hydrocarbon receptor nuclear translocator, and the complex interacts with the HRE of target genes (6, 7). The importance of this mechanism is ascertained by the facts that vessel formation is hampered in HIF-1␣ Ϫ/Ϫ knock out mice (8) and that mutations in the vHL gene cause hereditary cancer syndrome associated with dysregulated angiogenesis and up-regulation of hypoxia-sensitive genes.Cyclosporin A (CsA) is a potent immunosuppressive agent used after organ transplantation and in the treatment of several autoimmune diseases. CsA is well known to be nephrotoxic probably as a consequence of the constriction of renal vessels and of the resulting hypoxia. Circumstantial evidence further suggests that CsA interferes with the hypoxic signaling cascade. (i) Maruyama et al. (9) reported that CsA inhibited vascular endothelial growth factor production by human lymphocytes. (ii) CsA inhibits erythropoietin production in anemic mice (10). (iii) Kang et al. (11) reported that vascular endothelial growth factor reverses some of the post-CsA-mediated hypertension and nephropathy in the rat. (iv) Erythropoietin deficiency has been proposed as a cause of the anemia observed in children following cardiac transplantation (12). These would suggest that CsA inhibits the cellular responses that are mediated by HIF-1␣ and HRE.In the present study, we examine the possible influence of CsA on the hypoxic signaling. Results show that CsA inhibits hypoxia-induced gene transcription by preventing hypoxia-induced and ODD-dependent stabilization of HIF-1␣. We also show that CsA stimulates a kidney prolyl hydroxylase activity that specifically modifies Pro-564 in the ODD domain of HIF-1␣. MATERIALS AND METHODSMaterials-Culture medium, restriction, and ...

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“…Western Analysis-Schwann cells were cultured and transfected as described and 18 h later, mitochondrially enriched fractions were prepared as described (20). Briefly, each plate was rinsed twice in cold phosphate-buffered saline before adding homogenization buffer (17 mM MOPS, 2.5 mM EDTA, 250 mM sucrose, 0.1 mM phenylmethylsulfonyl fluoride, 5 g/ml leupeptin, and 5 g/ml aprotinin).…”

Section: Methodsmentioning

confidence: 99%

Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor

Linggi

Burke

Williams

et al. 2005

Journal of Biological Chemistry

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Activation of the p75 neurotrophin receptor leads to a variety of effects within the nervous system, including neuronal apoptosis. Both c-Jun N-terminal kinase (JNK) and the tumor suppressor p53 have been reported to be critical for this receptor to induce cell death; however, the mechanisms by which p75 activates these pathways is undetermined. Here we report that the neurotrophin receptor interacting factor (NRIF) is necessary for p75-dependent JNK activation and apoptosis. Upon nerve growth factor withdrawal, nrif؊/؊ sympathetic neurons underwent apoptosis, whereas p75-mediated death was completely abrogated. The lack of cell death correlated with a lack of JNK activation in the nrif؊/؊ neurons, suggesting that NRIF is a selective mediator for p75-dependent JNK activation and apoptosis. Moreover, we document that NRIF expression is sufficient to induce cell death through a mechanism that requires p53. Taken together, these results establish NRIF as an essential component of the p75 apoptotic pathway.The p75 neurotrophin receptor is a pleiotropic signaling molecule that regulates cellular survival, neurite outgrowth, and myelin formation (1). This founding member of the tumor necrosis factor receptor superfamily can directly bind all of the neurotrophins, including nerve growth factor (NGF), 1 brainderived neurotrophic factor (BDNF), and neurotrophin-3 and -4 (NT-3, NT-4), but it also functions as a co-receptor in a variety of protein complexes. p75 can interact with TrkA to form a high affinity neurotrophin binding site (2) and enhance survival signaling (3). It can also associate with the Nogo receptor and Lingo-1 and, upon interaction with myelin proteins, block neurite outgrowth (4, 5), and, together with Sortilin, the neurotensin 3 receptor, it binds the proform of NGF and initiates apoptosis (6). The divergent cellular responses depend on the receptor complex as well as the cellular context. For example, sympathetic neurons of superior cervical ganglia undergo a period of programmed cell death during ontogenesis, and NGF, supplied by the tissues innervated, prevents the loss of these neurons through binding to a p75-TrkA complex (7). In contrast, specific activation of p75 (8) or a p75-sortilin complex (6) induces apoptosis in the neurons. Genetic deletion of p75 prevents the normal period of cell death in the developing superior cervical ganglia (8, 9), thus demonstrating the key role of this receptor in regulating the survival of this neuronal population.How p75 initiates this variety of biological effects is not well understood; however, the stress kinase c-Jun N-terminal kinase, JNK, has been suggested to play a role in mediating this apoptotic signal. Neurotrophin activation of JNK through p75 correlates with the induction of cell death (43) and inhibition of the kinase prevents the receptor from killing (23, 10). Interestingly, c-Jun, the downstream target of the kinase, is not required for the receptor to activate apoptosis (11); however, other JNK substrates have been implicated in the p75 death ...

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SM-20 Is a Novel Mitochondrial Protein That Causes Caspase-dependent Cell Death in Nerve Growth Factor-dependent Neurons

Cited by 91 publications

References 26 publications

Falkor, a novel cell growth regulator isolated by a functional genetic screen

Falkor, a novel cell growth regulator isolated by a functional genetic screen

Cyclosporin A Prevents the Hypoxic Adaptation by Activating Hypoxia-inducible Factor-1α Pro-564 Hydroxylation

Neurotrophin Receptor Interacting Factor (NRIF) Is an Essential Mediator of Apoptotic Signaling by the p75 Neurotrophin Receptor

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