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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progesterone inhibits the proliferation of normal breast epithelial cells in vivo, as well as breast cancer cells in vitro. But the biologic mechanism of this inhibition remains to be determined. We explored the possibility that an antiproliferative activity of progesterone in breast cancer cell lines is due to its ability to induce apoptosis. Since p53, bcl-2 and survivin genetically control the apoptotic process, we investigated whether or not these genes could be involved in the progesterone-induced apoptosis. We found a maximal 90% inhibition of cell proliferation with T47-D breast cancer cells after exposure to 10 microM progesterone for 72 h. Control progesterone receptor negative MDA-231 cancer cells were unresponsive to 10 microM progesterone. The earliest sign of apoptosis is translocation of phosphatidylserine from the inner to the outer leaflet of the plasma membrane and can be monitored by the calcium-dependent binding of annexin V in conjunction with flow cytometry. After 24 h of exposure to 10 microM progesterone, cytofluorometric analysis of T47-D breast cancer cells indicated 43% were annexin V-positive and had undergone apoptosis and no cells showed signs of cellular necrosis (propidium iodide negative). After 72 h of exposure to 10 microM progesterone, 48% of the cells had undergone apoptosis and 40% were annexin V positive/propidium iodide positive indicating signs of necrosis. Control untreated cancer cells did not undergo apoptosis. Evidence proving apoptosis was also demonstrated by fragmentation of nuclear DNA into multiples of oligonucleosomal fragments. After 24 h of exposure of T47-D cells to either 1 or 10 microM progesterone, we observed a marked down-regulation of protooncogene bcl-2 protein and mRNA levels. mRNA levels of survivin and the metastatic variant CD44 v7-v10 were also downregulated. Progesterone increased p53 mRNA levels. These results demonstrate that progesterone at relative high physiological concentrations, but comparable to those seen in plasma during the third trimester of human pregnancy, exhibited a strong antiproliferative effect on breast cancer cells and induced apoptosis.
Mol Cell Biochem 1999 Dec
PMID:Bcl-2, survivin and variant CD44 v7-v10 are downregulated and p53 is upregulated in breast cancer cells by progesterone: inhibition of cell growth and induction of apoptosis. 1070 95

Survivin is a novel inhibitor of apoptosis. It has been reported that survivin is expressed during fetal development and in cancer tissues, but its expression has not been reported in adult tissues. We investigated the expression of survivin in the endometria of women with regular menstrual cycles using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry, and compared these findings with Bcl-2, an apoptosis inhibitor. Survivin mRNA was detected by RT-PCR in all samples (nine of nine) of endometrium during the secretory phase, but in only four out of seven samples from endometrium during the proliferative phase, and in none of the atrophic endometrium. Immunohistochemistry demonstrated a survivin protein expression that was strongest in the nuclei of glandular epithelial cells during the late secretory phase. In the proliferative phase, glandular epithelial cells were not stained for survivin. The cyclic changes of survivin and Bcl-2 showed an inverse relationship, with Bcl-2 expression being strongest in the proliferative phase and survivin expression being strongest in the secretory phase. The up-regulation of survivin expression may be due to the concurrent rise in progesterone concentrations during the normal menstrual cycle. Moreover, survivin could play an important role independent of Bcl-2 in physiological homeostasis in the normal endometrium.
Mol Hum Reprod 2000 Jun
PMID:Expression of survivin and Bcl-2 in the normal human endometrium. 1082 70

The coupling of apoptosis (programmed cell death) to the cell division cycle is essential for homeostasis and genomic integrity. Here, we report the crystal structure of survivin, an inhibitor of apoptosis, which has been implicated in both control of cell death and regulation of cell division. In addition to a conserved N-terminal Zn finger baculovirus IAP repeat, survivin forms a dimer through a symmetric interaction with an intermolecularly bound Zn atom located along the molecular dyad axis. The interaction of the dimer-related C-terminal alpha helices forms an extended surface of approximately 70 A in length. Mutagenesis analysis revealed that survivin dimerization and an extended negatively charged surface surrounding Asp-71 are required to counteract apoptosis and preserve ploidy. These findings may provide a structural basis for a dual role of survivin in inhibition of apoptosis and regulation of cell division.
Mol Cell 2000 Jul
PMID:Crystal structure and mutagenic analysis of the inhibitor-of-apoptosis protein survivin. 1094 38

Survivin is a mitotic spindle-associated protein involved in linking mitotic spindle function to activation of apoptosis in mammalian cells. The structure of the full-length human survivin has been determined by X-ray crystallography to 2.7 A. Strikingly, the structure forms a very unusual bow tie-shaped dimer. It does not dimerize through a C-terminal coiled-coil, contrary to sequence analysis prediction. The C-terminal helices contain hydrophobic clusters with the potential for protein-protein interactions. The unusual shape and dimensions of survivin suggest it serves an adaptor function through its alpha-helical extensions.
Mol Cell 2000 Jul
PMID:Crystal structure of human survivin reveals a bow tie-shaped dimer with two unusual alpha-helical extensions. 1094 39

Baculoviral IAP repeat proteins (BIRPs) may affect cell death, cell division, and tumorigenesis. The C. elegans BIRP BIR-1 was localized to chromosomes and to the spindle midzone. Embryos and fertilized oocytes lacking BIR-1 had defects in chromosome behavior, spindle midzone formation, and cytokinesis. We observed indistinguishable defects in fertilized oocytes and embryos lacking the Aurora-like kinase AIR-2. AIR-2 was not present on chromosomes in the absence of BIR-1. Histone H3 phosphorylation and HCP-1 staining, which marks kinetochores, were reduced in the absence of either BIR-1 or AIR-2. We propose that BIR-1 localizes AIR-2 to chromosomes and perhaps to the spindle midzone, where AIR-2 phosphorylates proteins that affect chromosome behavior and spindle midzone organization. The human BIRP survivin, which is upregulated in tumors, could partially substitute for BIR-1 in C. elegans. Deregulation of bir-1 promotes changes in ploidy, suggesting that similar deregulation of mammalian BIRPs may contribute to tumorigenesis.
Mol Cell 2000 Aug
PMID:The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. 1098 70

The human neuronal apoptosis inhibitory protein (NAIP) gene has been discovered as a candidate gene for spinal muscular atrophy, a genetic disorder characterized by motor neuron loss in the spinal cord. The telomeric NAIP gene on human chromosome 5 is deleted together with survival motor neurons (SMN) in many cases of the most severe forms of the disorder. NAIP, c-IAP1 (inhibitor of apoptosis-1), c-IAP2, X-IAP, survivin and Apollon comprise the mammalian inhibitors of the apoptosis family and contain an N-terminal domain with 1-3 imperfect repeats of an approximately 65 amino acids domain named the baculovirus IAP repeat (BIR) motif. We identified six NAIP genes in the mouse genome which were found to be expressed in a broad range of tissues. Furthermore, we have investigated the effects of NAIP in the rat pheochromocytoma PC12 cell line. These cells differentiate in the presence of nerve growth factor (NGF) into cells that resemble sympathetic neurons. We observed that NAIP overexpression impaired NGF-induced neurite outgrowth. The BIR motifs of NAIP (residues 1-345) were not required for this effect. However, the BIR domains of NAIP were essential to prevent apoptosis in PC12 cells after NGF deprivation or TNF-alpha receptor stimulation. Expression of full-length but not BIR-deleted-NAIP protects against cell death. This correlates with reduced activity of the cell death effector protease, caspase-3, in lysates of NAIP-PC12 cells, as measured by cleavage of the fluorogenic tetrapeptide substrate Asp-Glu-Val-Asp. Thus, unregulation of cellular differentiation and/or caspase suppression may contribute to motoneuron dysfunction and cell death in spinal muscular atrophy where NAIP is mutated.
Hum Mol Genet 2000 Oct 12
PMID:The neuronal apoptosis inhibitory protein suppresses neuronal differentiation and apoptosis in PC12 cells. 1103 Jul 53

Sporadic adenomas are said to exhibit an orderly growth pattern with a reversal of proliferative and apoptotic cell distribution as compared with normal colonic crypts. Dysplastic polyps of patients with ulcerative colitis (UC) may represent dysplasia-associated lesions or masses (DALM) with a high associated cancer risk, or, alternatively, may represent sporadic adenomas. Histologic criteria to differentiate between sporadic adenomas and DALM have not focused on the balance between cell renewal and cell loss. The expression of the novel anti-apoptosis gene product, survivin, and the proliferation markers, Ki-67 and Y-box binding protein (YB-1), were investigated by immunohistochemical localization in sporadic adenomas and DALM lesions of patients with UC. In adenomas, KI-67 was expressed preponderantly at the luminal aspect of the polyp, whereas its expression was diffuse in DALM. Survivin was detected diffusely in both adenomas and DALM. YB-1 showed positive staining in the deep aspect of adenomatous glands but only to a minor degree at the surface, whereas both deep and diffuse expression patterns of YB-1 were seen in DALM. The authors conclude that DALM and sporadic adenomas exhibit different patterns of cellular proliferation and that molecular markers of cell proliferation, Ki-67 and YB-1, may be useful to distinguish sporadic adenomas from DALM. However, the similar expression of survivin suggests that the underlying mechanisms that regulate apoptotic cell death are uniform in these lesions.
Appl Immunohistochem Mol Morphol 2001 Jun
PMID:Expression of survivin, YB-1, and KI-67 in sporadic adenomas and dysplasia-associated lesions or masses in ulcerative colitis. 1139 32

Deregulated expression of inhibitors of apoptosis (programmed cell death) may contribute to cancer by aberrantly extending cell viability and facilitating the insurgence of resistance to therapy. In this study, we investigated the potential expression and prognostic significance of the apoptosis inhibitor survivin in squamous cell carcinoma (SCC). A series of 135 cases of SCC including 46 oral SCC and 89 cutaneous SCC was analyzed for survivin expression by immunohistochemistry and Western blotting. Survivin was found in 57 cases (64%) of skin SCC and 26 cases (56%) of oral SCC, with weighted survivin scores ranging from 1 to 12. In contrast, normal oral epithelium, normal skin epithelium, and skin annexa did not express survivin. Survivin expression significantly (P < 0.05) segregated with high-grade and undifferentiated tumors with size >1.5 cm and invariably associated with lymph node metastasis. These data suggest that survivin expression may predictively identify cases of SCC with more aggressive and invasive clinical phenotype, potentially warranting closer follow-up protocols.
Exp Mol Pathol 2001 Jun
PMID:Expression of the apoptosis inhibitor survivin in aggressive squamous cell carcinoma. 1141 3

Survivin is a member of the inhibitor of apoptosis protein (IAP) family. The expression of survivin has not been reported in differentiated normal tissues, but it has been observed in many cancerous tissues. Recent studies have revealed that survivin may correlate with the chemo-radio resistance of certain malignant cells. In the present study, the correlation between the occurrence of apoptosis and the level of expression of survivin messenger RNA (mRNA) was investigated in a gastric cancer cell line (MKN-45) and in patients with advanced gastric cancer during cisplatin (CDDP) treatment. In the gastric cancer cell line, the percentage of apoptotic cells (apoptotic index: AI) did not change after 48 h incubation with low-dose CDDP (1 microg/ml), whereas the AI explosively increased between 12 and 24 h treatment with high-dose CDDP (10 microg/ml). Relative levels of expression of survivin mRNA and survivin protein increased after low- and high-dose CDDP treatment. Survivin mRNA was not detected in normal gastric mucosas. Also, in 13 patients with advanced gastric cancer who underwent CDDP-based preoperative chemotherapy, survivin mRNA was detected in only 2 cases (15.4%). Survivin mRNA was observed in the resected tumor specimens of two cases. No significant correlation between survivin mRNA expression and the occurrence of apoptosis in resected tumors or between survivin mRNA expression and patient survival was observed. These findings indicate that survivin may play an important role for the chemoresistance of this cancer cell line. However, the clinical importance of survivin expression remains unclear in patients with gastric cancer.
Int J Mol Med 2001 Dec
PMID:Changes in survivin messenger RNA level during cisplatin treatment in gastric cancer. 1171 83

Despite its genetic complexity and multifactoriality, two processes appear almost universally compromised in cancer: the control of cell proliferation and the regulation of cell lifespan. Survivin is a recently described molecule that has been implicated in both processes, and is overexpressed in most human cancers. The exploitation of the survivin signaling pathway might provide important predictive and prognostic clues in cancer diagnosis, and offer new therapeutic alternatives for cancer treatment.
Trends Mol Med 2001 Dec
PMID:The molecular basis and potential role of survivin in cancer diagnosis and therapy. 1173 16


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