Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Virtually all cell populations in the vertebrate nervous system undergo massive "naturally-occurring" or "programmed" cell death (PCD) early in development. Initially neurons and glia are overproduced followed by the demise of approximately one-half of the original cell population. In this review we highlight current hypotheses regarding how large-scale PCD contributes to the construction of the developing nervous system. More germane to the theme of this symposium, we emphasize that the survival of cells during PCD depends critically on their ability to access "trophic" molecular signals derived primarily from interactions with other cells. Here we review the cell-cell interactions and molecular mechanisms that control neuronal and glial cell survival during PCD, and how the inability of such signals to suppress PCD may contribute to cell death in some diseases such as spinal muscular atrophy. Finally, by using neurotrophic factors (e.g. CNTF, GDNF) and genes that control the cell death cascade (e.g. Bcl-2) as examples, we underscore the importance of studying the mechanisms that control neuronal and glial cell survival during normal development as a means of identifying molecules that prevent pathology-induced cell death. Ultimately this line of investigation could reveal effective strategies for arresting neuronal and glial cell death induced by injury, disease, and/or aging in humans.
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PMID:Programmed cell death in the developing nervous system. 894 15

Childhood spinal muscular atrophy (SMA) is a common recessive autosomal disorder that results in degeneration of lower motor neurons. The identification of the disease gene, Survival of Motor Neuron (SMN), was a major advance in understanding the molecular basis underlying this devastating neuromuscular disease. This finding has greatly improved the genetic counselling of SMA families. Recently, biochemical studies demonstrated its involvement in the biogenesis of spliceosomal snRNPs, suggesting a critical role of SMN in RNA processing. Surprisingly, other studies showed a putative role of SMN in an anti-apoptotic pathway involving Bcl-2. The function of SMN protein is not fully understood. These observations emphasized the difficulty in elucidating the function of any novel protein. Therefore, multidisciplinary approaches are required to understand the pathogenesis of SMA.
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PMID:The role of the SMN gene in proximal spinal muscular atrophy. 973 73

Mutations in the gene encoding survival motor neuron (SMN) protein are found in > 98% of patients with autosomal-recessive spinal muscular atrophy. We investigated the possible role of SMN in normal and abnormal human muscle by immunostaining biopsies of 20 patients with various neuromuscular diseases using monoclonal antibodies against SMN. SMN was strongly expressed cytoplasmically in chronic peripheral neuropathies, in about 80% of chronically denervated, very atrophic muscle fibers containing clumps of TUNEL-positive pyknotic nuclei: about 60% of those fibers also had cytoplasmic Bcl-2 and Bax immunoreactivity. In regenerating muscle fibers of various myopathies SMN co-localized with desmin, Bcl-2 and Bax; it was also present at the postsynaptic domain of normal human neuromuscular junctions. Thus, SMN may play a role in normal and pathological processes of adult human muscle fibers.
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PMID:Localization of survival motor neuron protein in human apoptotic-like and regenerating muscle fibers, and neuromuscular junctions. 1050 49

Congestive heart failure is characterized by a skeletal muscle myopathy with muscle bulk loss. The mechanisms responsible for these changes are not clear at present. We have investigated the role of apoptosis in the rat "slow" soleus muscle during the development of heart failure, which was induced by injection of monocrotaline (30 mg/kg). We looked at the time course of apoptosis by studying six animals at each of the following time points: 0, 17, 24, and 30 days. We found a decreased expression of the antiapoptotic protein Bcl-2, which was accompanied by a rise of proapoptotic caspase-3. Ubiquitin levels did not change. DNA nick-end labeling showed an increased number of apoptotic nuclei both in myofibers and interstitial cells when heart failure occurred. At variance with previous observations in the fast-twitch tibialis anterior muscle in the same animals, in which tumor necrosis factor-alpha (TNF-alpha) increased at the time that apoptosis occurred, the magnitude of apoptosis is lower in soleus muscle and there is no appearance of muscle atrophy. In soleus muscle, apoptosis is accompanied by activation of the caspase-3 system. There is no activation of the TNF-alpha- and ubiquitin-dependent protein waste. In conclusion, slow muscles are less prone to develop apoptosis than fast muscles. Muscle atrophy appears earlier in these latter ones.
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PMID:Apoptosis and atrophy in rat slow skeletal muscles in chronic heart failure. 1056 91

The SMN gene is implicated in spinal muscular atrophy (SMA), and its product has been shown to interact with Bcl-2 protein to enhance its anti-apoptotic activity. In this study, we determined the regions that were essential for the interaction of Bcl-2 and SMN by co-immunoprecipitation of deletion mutants. Bcl-2 lacking its amino-terminal 20 amino acid residues or its carboxyl-terminal membrane-anchoring domain showed no or greatly reduced binding with SMN, respectively. However, Bcl-2 lacking other regions could still bind to SMN. Because Bcl-2 lacking the membrane-anchoring domain could bind to SMN in a yeast two-hybrid system, the amino-terminal region of Bcl-2 seems to be the most important domain for binding with SMN. A fragment of SMN encoded by exon 6 could bind to Bcl-2, but SMN lacking this region could not. From these results, we concluded that Bcl-2 and SMN proteins bound with each other at the amino-terminal region near the BH4 domain of Bcl-2 and the region encoded by exon 6 of SMN, both regions known to be important for their function.
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PMID:Regions essential for the interaction between Bcl-2 and SMN, the spinal muscular atrophy disease gene product. 1077 22

The survival motor neuron (SMN) gene is deleted or mutated in over 98% of spinal muscular atrophy patients who show specific motoneuron loss. By performing transfection experiments with rat smn cDNA, we show that two isoforms of SMN with Mr of 32 kDa and 35 kDa are produced by the same cDNA. In cultured motoneurons, both forms colocalize in coiled bodies and not in GEMS bodies as shown for HeLa cells. Subcellular fractionation of cells acutely dissociated from rat embryonic ventral spinal cord shows that the two SMN isoforms have a different subcellular localization, namely, that the 32 kDa isoform is enriched in the cytosol, whereas the 35 kDa isoform is segregating in the microsomal fraction. We show that the 35 kDa isoform of SMN is part of an insoluble complex but is absent from the cytoplasmic membranes and from the mitochondria. Immunostaining studies show that neither SMN isoform colocalizes with Bcl-2, the mitochondrial antiapoptotic protein suggested to bind to SMN in HeLa cells. Our results show that the isoforms of SMN protein have different subcellular localization and may therefore play independent biological roles. Moreover, the absence of colocalization of SMN with Bcl-2 in motoneurons suggests that some of the interactors of SMN may vary depending on the cell type, and this underscores the importance of identifying motoneuron-specific SMN interactors.
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PMID:Expression and subcellular localization of two isoforms of the survival motor neuron protein in different cell types. 1105 3

We reported finding that apoptosis occurred in skeletal muscle in the early stage after implantation. In the present study, we investigated expression of the apoptosis-related proteins Bax and Bcl-2 to determine the mechanism of the apoptosis. In the early stage of tumor bearing, 20 days after implantation, lean body mass (LBM) was reduced by 5.06 +/- 1.10% in the tumor-bearing group, compared with an increase of 4.96 +/- 1.26% in the control group. The apoptotic index (AI) of the skeletal muscle in the tumor-bearing group increased to 40.5 +/- 3.20% but was 0% in the control group, and Bax expression was strongly positive in 5 of the 10 rabbits in the tumor-bearing group, and significantly stronger than in the control group (P = 0.0002). In the late stage of tumor bearing, 40 days after implantation, the AI had declined to 0.93 +/- 0.96% in the tumor-bearing group, but was still 0% in the control group. Bax expression was rarely detected in either the tumor-bearing group or the control group, and there was no significant difference between the two groups (P = 0.706). No significant changes in Bcl-2 were observed in either group. The above results showed that apoptosis via Bax played a role in muscle wasting associated with progression of the malignant tumor. However, the apoptosis and expression of Bax were seen only in the early stage, within 20 days after implantation, not in the late stage. This suggested that the muscle wasting in the early stage might be caused by a different mechanism from that in the late stage.
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PMID:Expression of apoptosis regulatory proteins in the skeletal muscle of tumor-bearing rabbits. 1142 51

Although cytokine-induced nuclear factor kappaB (NF-kappaB) pathways are involved in muscle wasting subsequent to disease, their potential role in disuse muscle atrophy has not been characterized. Seven days of hind limb unloading led to a 10-fold activation of an NF-kappaB-dependent reporter in rat soleus muscle but not the atrophy-resistant extensor digitorum longus muscle. Nuclear levels of p50 were markedly up-regulated, c-Rel was moderately up-regulated, Rel B was down-regulated, and p52 and p65 were unchanged in unloaded solei. The nuclear IkappaB protein Bcl-3 was increased. There was increased binding to an NF-kappaB consensus oligonucleotide, and this complex bound antibodies to p50, c-Rel, and Bcl-3 but not other NF-kappaB family members. Tumor necrosis factor alpha (TNF-alpha) and TNF receptor-associated factor 2 protein were moderately down-regulated. There was no difference in p38, c-Jun NH(2)-terminal kinase or Akt activity, nor were activator protein 1 or nuclear factor of activated T cell-dependent reporters activated. Thus, whereas several NF-kappaB family members are up-regulated, the prototypical markers of cytokine-induced activation of NF-kappaB seen with disease-related wasting are not evident during disuse atrophy. Levels of an anti-apoptotic NF-kappaB target, Bcl-2, were increased fourfold whereas proapoptotic proteins Bax and Bak decreased. The evidence presented here suggests that disuse muscle atrophy is associated with activation of an alternative NF-kappaB pathway that involves the activation of p50 but not p65.
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PMID:Activation of an alternative NF-kappaB pathway in skeletal muscle during disuse atrophy. 1191 55

The mouse mutant "motoneuron disease 2" (MND2, mnd2 on Chr 6) was originally characterized as a spinal muscular atrophy (SMA) because degenerating motoneurons were observed in late stages of the disease. MND2 mutants exhibit a progressive phenotype with neurological symptoms that begin at postnatal day (dP) 20 and include involuntary movements, abnormal postures, akinesis, and death between dP 30 and 40. Unexpectedly, there was no induction of acetylcholine receptor alpha subunit mRNA in skeletal muscle of MND2 mice, an indicator of muscle denervation due to motoneuron loss. Rather, we found a massive loss of striatal neurons beginning at dP 25. Histochemical and ultrastructural analysis revealed nuclear pyknosis, chromatin condensation, and organelle disintegration, combined features of apoptosis and necrosis, characteristic for excitotoxic cell death. Striatal neurodegeneration was accompanied by a pronounced astrogliosis and activation of microglia with macrophage morphology. Motor abnormalities and neuronal loss in MND2 mice were not prevented by neuronal overexpression of a Bcl-2 transgene. Transcripts of several cytokines, including Interleukin-1beta and tumor necrosis factor alpha, were upregulated in the CNS, as well as in lung and spleen, indicating that the mnd2 mutation causes additional pathological effects outside the CNS. Since a 50% reduction in the number of striatal neurons is sufficient to account for the neurological phenotype of MND2 mice, MND2 may be classified as striatal atrophy rather than a primary motor neuron disease. Thus, MND2 mutant mice may provide useful insights into molecular events underlying striatal cell death.
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PMID:Progressive loss of striatal neurons causes motor dysfunction in MND2 mutant mice and is not prevented by Bcl-2. 1200 62

A neuropathological study of Holstein-Friesian calves with spinal muscular atrophy (SMA) demonstrated decreased numbers of motor neurons in the brachial and lumbo-sacral regions of the spinal cord, together with swelling and accumulation of phosphorylated neurofilaments, and neuronophagia in most of the remaining motor neurons. The pyramidal tracts, motor cortex and thalamus were not affected. Synaptophysin immunohistochemistry revealed a marked reduction of punctate terminals but only around swollen neurones, suggesting loss of terminal afferents on motor neurons at advanced stages of the degenerative process. An immunohistochemical study of proteins linked with cell death and cell survival demonstrated reduced expression of Fas, Fas-L, Bcl-2 and Bax in swollen motor neurons. Punctate cytochrome C immunoreactivity, consistent with mitochondrial localization, was detected in the soma of normal motor neurons, but not in swollen motor neurons. Finally, no labelling of motor neurons with antibodies to cleaved (active) caspase-3 (17kD) was detected, suggesting a lack of involvement of the apoptotic pathways in motor neuron death. Taken together, the present findings point to necrosis as a major cause of motor neuron death in the advanced stages of SMA in Holstein-Friesian calves.
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PMID:Cell death and decreased synaptic protein expression in the ventral horn of Holstein-Friesian calves with spinal muscular atrophy. 1263 90


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