A Mitochondrial Protein, Bit1, Mediates Apoptosis Regulated by Integrins and Groucho/TLE Corepressors
ABSTRACT A delicate balance of signals regulates cell survival. One set of these signals is derived from integrin-mediated cell adhesion to the extracellular matrix (ECM). Loss of cell attachment to the ECM causes apoptosis, a process known as anoikis. In searching for proteins involved in cell adhesion-dependent regulation of anoikis, we identified Bit1, a mitochondrial protein that is released into the cytoplasm during apoptosis. Cytoplasmic Bit1 forms a complex with AES, a small Groucho/transducin-like enhancer of split (TLE) protein, and induces cell death with characteristics of caspase-independent apoptosis. Cell attachment to fibronectin counteracts the apoptotic effect of Bit1 and AES. Increasing Bit1 expression enhances anoikis, while suppressing the expression reduces it. Thus, we have elucidated an integrin-controlled pathway that is, at least in part, responsible for the cell survival effects of cell-ECM interactions.
SourceAvailable from: Olaf Ninnemann[Show abstract] [Hide abstract]
ABSTRACT: To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). We characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts. In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts. We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease.12/2014; 1(12):1024-35. DOI:10.1002/acn3.149
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ABSTRACT: Few studies have referred to the implication of anoikis processes following hormonal treatment. No data are available on the influence of estrogen in ovarian cancer anoikis. To gain insights into the effects and mechanism of estrogen in ovarian cancer cells, we have carried out studies on the anoikis of ovarian cancer cells treated with estrogen and on the pathways involved. We observed an anti-anoikis role of E2 in suspended Caov-3 cells, and this was mainly due to the decreasing of Bit1 level in cytosol. We also found that estrogen receptor α (ERα) was the main mediator involved in this process. To study the signaling pathways well, phosphatidylinositol 3-kinase (PI3K)/AKT were further investigated. Results demonstrated that the decreasing of the Bit1 level in cytosol mediated by E2 binding to ERα was mainly through PI3K/AKT pathways. Overall, these findings disclose a new perspective for estrogen on ovarian cancer therapy.DNA and Cell Biology 09/2014; DOI:10.1089/dna.2014.2453 · 1.99 Impact Factor
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ABSTRACT: Fibrin plays an important role in lung metastasis. Here we show that fibrin promotes colony formation in primary kidney tumor cells from patients with kidney metastasis. In addition, we found that inhibition of fibrin formation with the thrombin inhibitor hirudin in nude mice in vivo significantly reduced the metastatic outgrowth of kidney tumor cells. Colony formation was significantly more efficient in tumor cells embedded in fibrin compared to matrigel and this effect correlates with the capacity of tumor cells to assemble a fibronectin matrix and generate stress fibers. Interestingly, stress fiber formation in fibrin was a specific function of metastatic kidney tumor cells while non-metastatic cells remained round. Inhibition of stress fiber formation with the Rho kinase inhibitor Y-27632, in turn, reduced fibronectin matrix assembly and colony formation in fibrin suggesting that spreading is a critical mechanism for the outgrowth of metastatic kidney tumor cells. Overall, our results indicate that adhesive interactions with fibrin play an important role for the progression of renal cell carcinoma and that inhibiting these interactions could be a promising strategy for treatment and prevention of kidney cancer metastasis.