Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate apoptosis in HC11 mammary epithelial cells, we compared the gene expression profiles of actively growing and serum-starved apoptotic cells using a mouse apoptosis gene array and 33P-labeled cDNA prepared from the RNA of the two cultures. Analysis of the arrays showed that expression of several genes such as clusterin, secreted frizzled related protein mRNA (sFRP-1), CREB-binding protein (CBP), and others was higher in the apoptotic cells whereas expression of certain genes including survivin, cell division cycle 2 homolog A (CDC2), and cyclin A was lower. These expression patterns were confirmed by RT-PCR and/or Northern analyses. We compared the expression of some of these genes in the mouse mammary gland under various physiological conditions. The expression levels of genes (clusterin, CBP, and M6P-R) up-regulated in apoptotic conditions were higher at involution than during lactation. On the other hand, genes (Pin, CDC2) downregulated in apoptotic conditions were relatively highly expressed in virgin and pregnant mice. We conclude that certain genes such as clusterin, sFRP-1, GAS1 and CBP are induced in apoptotic mammary epithelial cells, and others are repressed. Moreover, the apoptosis array is an efficient technique for comparing gene expression profiles in different states of the same cell type.
Mol Cells 2005 Aug 31
PMID:Expression profiles of apoptosis genes in mammary epithelial cells. 1625 47

Ischemic preconditioning (IP) enhances vascular endothelial growth factor (VEGF), Bcl-2 and survivin expression after myocardial infarction (MI). Mechanisms of angiogenic and anti-apoptotic effects due to IP still remain unclear. The present study attempts to address whether GSK-3beta-beta-catenin signaling in turn interacts with T-cell transcription factor/lymphoid-enhancer binding factor (TCF/LEF) and regulates these genes in the ischemic preconditioned myocardium. In a rat MI model with permanent occlusion of left anterior descending coronary artery (LAD), IP (four cycles of 4-min of ischemia and 4-min of reperfusion) significantly phosphorylated and inhibited GSK-3beta and accumulated beta-catenin in the cytosol and nucleus. Wortmannin, a PI-3 kinase inhibitor, repressed this effect in our model. We examined whether pretreatment with GSK-3beta inhibitor lithium or SB216763, mimicked IP-mediated angiogenesis and cardioprotection. Lithium- or SB216763- treated rats revealed accumulation of cytosolic and nuclear beta-catenin. This was followed by increased TCF/LEF transcriptional activity and the upregulation of VEGF, Bcl-2 and survivin mRNA expression accompanied by reduction of apoptotic cardiomyocytes and endothelial cells and increased capillary density after MI. The results of this study demonstrate, first time that inhibition of GSK-3beta followed by accumulation of beta-catenin in the cytosol and nucleus has potent anti-apoptotic and angiogenic effects after MI and that the PI3-kinase/GSK-3beta/beta-catenin signaling pathway plays an important role in IP.
J Mol Cell Cardiol 2006 Jan
PMID:Glycogen synthase kinase-3beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium. 1628 8

The Forkhead box m1 (Foxm1) gene is critical for G(1)/S transition and essential for mitotic progression. However, the transcriptional mechanisms downstream of FoxM1 that control these cell cycle events remain to be determined. Here, we show that both early-passage Foxm1(-)(/)(-) mouse embryonic fibroblasts (MEFs) and human osteosarcoma U2OS cells depleted of FoxM1 protein by small interfering RNA fail to grow in culture due to a mitotic block and accumulate nuclear levels of cyclin-dependent kinase inhibitor (CDKI) proteins p21(Cip1) and p27(Kip1). Using quantitative chromatin immunoprecipitation and expression assays, we show that FoxM1 is essential for transcription of the mitotic regulatory genes Cdc25B, Aurora B kinase, survivin, centromere protein A (CENPA), and CENPB. We also identify the mechanism by which FoxM1 deficiency causes elevated nuclear levels of the CDKI proteins p21(Cip1) and p27(Kip1). We provide evidence that FoxM1 is essential for transcription of Skp2 and Cks1, which are specificity subunits of the Skp1-Cullin 1-F-box (SCF) ubiquitin ligase complex that targets these CDKI proteins for degradation during the G(1)/S transition. Moreover, early-passage Foxm1(-)(/)(-) MEFs display premature senescence as evidenced by high expression of the senescence-associated beta-galactosidase, p19(ARF), and p16(INK4A) proteins. Taken together, these results demonstrate that FoxM1 regulates transcription of cell cycle genes critical for progression into S-phase and mitosis.
Mol Cell Biol 2005 Dec
PMID:Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. 1631 12

Proteasome inhibition following DNA damage results in the synergistic induction of apoptosis via a nuclear factor-kappaB-independent mechanism. In this study, we identify the role of p53 in mediating apoptosis by the sequence-specific treatment involving the DNA-damaging, topoisomerase I-targeting drug SN-38 followed by the proteasome inhibitor PS-341 (SN-38-->PS-341). The p53-dependent sensitization of DNA damage-induced apoptosis by PS-341 is accompanied by persistent inhibition of proteasome activity and increased cytosolic accumulation of p53, including higher molecular weight forms likely representing ubiquitinated species. In contrast, pretreatment with PS-341 followed by treatment with SN-38 (PS-341-->SN-38), which leads to an antagonistic interaction, results in transient inhibition of proteasome activity and accumulation of significantly lower levels of p53 localized primarily to the nucleus. Whereas cells treated with PS-341-->SN-38 undergo G2 + M cell cycle arrest, cells treated with SN-38-->PS-341 exhibit a decreased G2 + M block with a concomitant increase in the sub-G1 population. Decreased accumulation of cells in the G2 + M phase of the cell cycle in SN-38-->PS-341-treated cells compared with PS-341-->SN-38-treated cells correlates with enhanced apoptosis and reduced expression of two p53-modulated proteins, 14-3-3sigma and survivin, both of which play critical roles in regulating G2 + M progression and apoptosis. The functional role of 14-3-3sigma or survivin in regulating the divergent function of p53 in response to SN-38-->PS-341 and PS-341-->SN-38 treatment in inducing apoptosis versus G2 + M arrest/DNA repair, respectively, was confirmed by targeted down-regulation of these proteins. These results provide insights into the mechanisms by which inhibition of proteasome activity modulates DNA damage-induced apoptosis via a p53-dependent pathway.
Mol Cancer Ther 2005 Dec
PMID:Sensitization of DNA damage-induced apoptosis by the proteasome inhibitor PS-341 is p53 dependent and involves target proteins 14-3-3sigma and survivin. 1637 3

In this study, we wanted to clarify the role of survivin-mediated survival signaling during G2 and M in tumor cells treated with DNA-damaging agents. As a cellular model, we selected MOLT-4 human T-cell lymphoblastic leukemia cells that overexpress survivin and nonfunctional p53. Treatment with melphalan, a classic DNA-damaging agent, led to the induction of the DNA damage checkpoint and growth arrest in the G2 phase of the cell cycle. Checkpoint abrogation by caffeine was accompanied by mitotic entry and rapid apoptotic cell death, whereas cells remaining in G2 remained viable during the same time interval. Unexpectedly, when the spindle checkpoint was activated following G2 abrogation, two different effects could be observed. If the microtubules of the melphalan-treated cells were destabilized by nocodazole, cells became arrested in prometaphase with low survivin levels and entered apoptosis. In contrast, if the microtubules of the melphalan-treated cells were stabilized by taxol, cells were still arrested in prometaphase, but apoptotic execution was inhibited. This effect is, most likely, directly mediated by survivin itself given its well-established antiapoptotic functions. In conclusion, depending on the way the spindle checkpoint was activated in cells with damaged DNA, cells could be either protected by survivin or die during mitosis. We suggest that the efficacy of DNA damage checkpoint abrogators used in combination with DNA-damaging agents may critically depend on whether DNA damage is able to invoke spindle checkpoint response and to activate survivin-associated survival signaling during mitosis.
Mol Cancer Ther 2005 Dec
PMID:Cross-talk between DNA damage and cell survival checkpoints during G2 and mitosis: pharmacologic implications. 1637 17

Two isoforms of cyclooxygenase (COX) are known, and to date most studies have implicated COX-2 in the development and progression of various human cancers. Increasing evidence suggests that COX-1 may also play a similar role. Indeed, we have recently observed that the dual COX-1/COX-2 inhibitor indomethacin induces apoptosis in human hepatocellular carcinoma (HCC) cell lines more effectively than the selective COX-2 inhibitors, possibly implicating COX-1 in HCC. In this study we investigated the expression of COX-1 in non-tumor and malignant human liver tissues, as well as the effects of the highly selective COX-1 inhibitor SC-560 on cell growth and apoptosis in human HCC cell lines. Expression of COX-1 was detected in nearly all the samples assayed, although with a high variability between non-tumoral (NT) and malignant tissues. The percentage of COX-1 positive cells was significantly higher in the NT tissues than in the tumors (p<0.0001). In well-differentiated HCC COX-1 expression was significantly higher than in the poorly-differentiated tissues (p<0.05). SC-560 showed a dose- and time-dependent inhibitory effect on HCC cell growth. The combination of the COX-1 inhibitor with nimesulide and CAY10404, two selective COX-2 inhibitors, resulted in additive effects on cell growth inhibition. SC-560 also inhibited colony formation in soft agar and induced apoptosis in HCC cells in a dose-dependent manner. Moreover, SC-560 decreased the levels of the anti-apoptotic proteins survivin and XIAP and activated caspase-3 and -7 in a dose- and time-dependent fashion. In conclusion, we report for the first time that the selective COX-1 inhibitor SC-560 exhibits anti-tumor and apoptotic effects in human HCC cells. Overall, our previous and present results suggest that both COX-1 and COX-2 inhibitors may have potential therapeutic implications in HCC patients.
Int J Mol Med 2006 Feb
PMID:The selective cyclooxygenase-1 inhibitor SC-560 suppresses cell proliferation and induces apoptosis in human hepatocellular carcinoma cells. 1639 22

Survivin is a member of the chromosomal passenger complex implicated in kinetochore attachment, bipolar spindle formation, and cytokinesis. However, the mechanism by which survivin modulates these processes is unknown. Here, we show by time-lapse imaging of cells expressing either green fluorescent protein (GFP)-alpha-tubulin or the microtubule plus-end binding protein GFP-EB1 that depletion of survivin by small interfering RNAs (siRNAs) increased both the number of microtubules nucleated by centrosomes and the incidence of microtubule catastrophe, the transition from microtubule growth to shrinking. In contrast, survivin overexpression reduced centrosomal microtubule nucleation and suppressed both microtubule dynamics in mitotic spindles and bidirectional growth of microtubules in midbodies during cytokinesis. siRNA depletion or pharmacologic inhibition of another chromosomal passenger protein Aurora B, had no effect on microtubule dynamics or nucleation in interphase or mitotic cells even though mitosis was impaired. We propose a model in which survivin modulates several mitotic events, including spindle and interphase microtubule organization, the spindle assembly checkpoint and cytokinesis through its ability to modulate microtubule nucleation and dynamics. This pathway may affect the microtubule-dependent generation of aneuploidy and defects in cell polarity in cancer cells, where survivin is commonly up-regulated.
Mol Biol Cell 2006 Mar
PMID:Survivin modulates microtubule dynamics and nucleation throughout the cell cycle. 1640 8

Survivin is an antiapoptotic gene, which is overexpressed in most human tumors and involved in mitotic checkpoint control. Recent evidence points to an essential role for heat shock protein 90 (Hsp90) in survivin function regulation. Although the survivin-Hsp90 association may promote tumor cell proliferation, it may also suggest new opportunities for the design of novel anticancer approaches. We evaluated the effect of small interfering RNA (siRNA)-mediated inhibition of survivin on the proliferative potential of prostate cancer cells and their sensitivity to the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). Human androgen-independent prostate cancer cell lines (DU145 and PC-3) were transfected with four 21-mer double-stranded siRNAs (100 nmol/L) directed against different portions of survivin mRNA. After transfection, cells were collected and analyzed for survivin mRNA and protein expression, cell proliferation rate, ability to undergo apoptosis, and sensitivity to 17-AAG. Transfection of prostate cancer cells with siRNAs induced a variable extent of inhibition of survivin mRNA expression (39-60% compared with controls), which was paralleled by a 38% to 75% reduction in survivin protein abundance. The three siRNAs able to induce the greatest inhibition of survivin expression also significantly reduced cell proliferation and enhanced the rate of apoptosis, with a concomitant increase in caspase-9 activity. Sequential treatment with siRNA and 17-AAG induced supra-additive antiproliferative effects in all cell lines, with an enhanced caspase-9-dependent apoptotic response. These findings suggest that combined strategies aimed at interfering with the survivin-Hsp90 connection may provide novel approaches for treatment of androgen-independent prostate cancer.
Mol Cancer Ther 2006 Jan
PMID:Silencing of survivin gene by small interfering RNAs produces supra-additive growth suppression in combination with 17-allylamino-17-demethoxygeldanamycin in human prostate cancer cells. 1643 77

Mutations in Ki-ras occur in approximately 30-50% of patients with adenocarcinoma (AC) of the lung. We previously reported the development of a bitransgenic mouse model that expressed the human Ki-ras(G12C) allele in a lung-specific, tetracycline-inducible manner and gave rise to benign lung tumors. In the current study, these benign tumors, which represent relatively early lesions in neoplastic progression, were analyzed for molecular alterations secondary to mutant Ki-ras expression to determine the gene(s) that contribute to adenoma (AD) development. Tumors were removed following doxycycline (DOX) treatment for 9 and 12 mo and examined for alterations in cell-cycle regulatory genes. Quantification of mRNA expression for cyclin D1, retinoblastoma, p16(Ink4a), p19(Arf), and survivin was carried out by real-time PCR. All of the tumors examined exhibited a mean reduction of approximately fivefold for the retinoblastoma gene (P < 0.02). Increased expression of both p19(Arf) and survivin were detected in a majority of the tumors examined (P < 0.01 and 0.001, respectively), but no change in cyclin D1 RNA expression was observed. A subset of the lung tumors (8/28) displayed reduced levels of p16(Ink4a) expression (P = 0.02). Immunohistochemical analysis confirmed the upregulation of p19(Arf) and survivin in all 10 of the lung tumors examined. However, increased staining for cyclin D1 was observed in the tumor tissue. In addition, increased levels of activated p53 were found in lung tumor tissues stained with an anti-phospho-p53 antibody, while an absence of staining was observed with an anti-phospho-pRb antibody in both normal control and tumor tissue. Analysis of the methylation status of p16(Ink4a) by methylation-specific PCR (MSP) demonstrated that seven of eight tumors exhibiting decreased expression of p16(Ink4a) had at least partial methylation of the promoter region. Single stranded conformational polymorphism (SSCP) analysis demonstrated that neither exons 1 or 2 of p16(Ink4a) nor exons 5-8 of p53 exhibited mutations. These data thus identify alterations in specific genes and pathways that combine with the mutation in Ki-ras to promote the formation of benign lung tumors and suggest potential targets for the development of novel chemotherapeutic and chemopreventive agents during the early stages of lung tumor progression.
Mol Carcinog 2006 Jul
PMID:Genetic and epigenetic alterations in lung tumors from bitransgenic Ki-rasG12C expressing mice. 1648 19

Embedded in the concept of targeted cancer therapy is the expectation that disabling a single oncogenic pathway will eliminate the tumor cells and leave the normal tissues unscathed. Although validated by clinical responses in certain malignancies, challenges exist to generalize this approach to most tumors, as multiple genetic lesions, chromosomal instability, insensitivity of the cancer stem cell compartment, and emergence of drug resistance complicate the identification and therapeutic exploitation of a single, driving oncogenic pathway. Instead, broader therapeutic prospects may be offered by targeting crossroad signaling networks that are selectively exploited in cancer and oversee multiple aspects of tumor cell maintenance. One such pathway is centered on survivin, a cancer gene that intersects cell proliferation, cell survival, and the cellular stress response. Several clinical trials targeting survivin with a collection of approaches from immunotherapy to small-molecule antagonists are currently under way. By simultaneously disabling multiple signaling circuitries, targeting survivin may provide a novel perspective in rational cancer therapy selective for specific cancer mechanisms but broadly applicable to disparate tumors regardless of their genetic makeup.
Mol Cancer Ther 2006 Mar
PMID:Targeted therapy by disabling crossroad signaling networks: the survivin paradigm. 1654 61


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>