Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic cancer has one of the worst prognoses of all human malignancies and the molecular mechanisms underlying this aggressive disease have been extensively investigated in the past years. Tyrosine kinase growth factor receptors and their ligands act to influence tumor cell growth, differentiation, invasion, metastasis, and angiogenesis. In pancreatic cancer a variety of these growth factor receptors and ligands are expressed at increased levels and this overexpression influences the clinical course of the disease. For example, the concomitant presence of the EGF receptor and its ligands EGF, TGF-alpha, and/or amphiregulin is associated with enhanced tumor aggressiveness and shorter survival periods following tumor resection. Furthermore, the growth inhibitory effects of the TGF-beta superfamily of serine-threonine kinase receptors and their ligands are often blocked in pancreatic cancer cells. In addition to these alterations, mutations of the p53 tumor-suppressor gene, the K-ras proto-oncogene, and the Smad4 gene are frequently present in these tumors. Taken together, the abundance of growth-promoting factors, the disturbance of growth inhibitory pathways, and the presence of gene mutations combine to give pancreatic cancer cells a distinct growth advantage which clinically results in rapid tumor progression and poor survival.
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PMID:Molecular aspects of pancreatic cancer and future perspectives. 1044 72

Human NDR1 (nuclear Dbf2-related) is a widely expressed nuclear serine-threonine kinase that has been implicated in cell proliferation and/or tumor progression. Here we present molecular characterization of the human NDR2 serine-threonine kinase, which shares approximately 87% sequence identity with NDR1. NDR2 is expressed in most human tissues with the highest expression in the thymus. In contrast to NDR1, NDR2 is excluded from the nucleus and exhibits a punctate cytoplasmic distribution. The differential localization of NDR1 and NDR2 suggests that each kinase may serve distinct functions. Thus, to identify proteins that interact with NDR1 or NDR2, epitope-tagged kinases were immunoprecipitated from Jurkat T-cells. Two uncharacterized proteins that are homologous to the Saccharomyces cerevisiae kinase regulators Mob1 and Mob2 were identified. We demonstrate that NDR1 and NDR2 partially colocalize with human Mob2 in HeLa cells and confirm the NDR-Mob interactions in cell extracts. Interestingly, NDR1 and NDR2 form stable complexes with Mob2, and this association dramatically stimulates NDR1 and NDR2 catalytic activity. In summary, this work identifies a unique class of human kinase-activating subunits that may be functionally analagous to cyclins.
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PMID:Human Mob proteins regulate the NDR1 and NDR2 serine-threonine kinases. 1506 4

Progression elevated gene-3 (PEG-3) is a novel rodent gene, identified and cloned by subtraction hybridization, that associates with transformation progression in virus- and oncogene-transformed rat embryo (RE) cells. Previous reports document that ectopic expression of PEG-3 in rodent or human tumor cells produces an aggressive transformed/tumorigenic phenotype. Moreover, PEG-3 expression in rodent tumor cells correlates directly with genomic instability, as indicated by chromosomal alterations and gene amplification, and it promotes angiogenesis. The present studies were designed to further elucidate the functional significance and role of PEG-3 in cancer progression with a specific focus on genomic instability and cancer invasion. Genomic instability was assessed by micronucleus assays and staining of centrosomes to define centrosomal amplification. Immunocytochemical observations revealed that overexpression of PEG-3 in transformed rodent cells induced a loss of chromosomes as established by the appearance of micronuclei and staining of the centrosomes with gamma-tubulin antibody, thereby confirming centrosome amplification. Overexpression of PEG-3 modulated the expression of several genes involved in centrosomal duplication, such as p21CIP1/WAF1/MDA-6, nucleophosmin (NPM), and aurora-A kinase. In vitro invasion of transformed rodent cells was augmented by PEG-3, which correlated with an increase in the transcription and activity of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), which play important roles in local invasion during cancer progression. These findings demonstrate that PEG-3 plays a central role in augmenting tumor progression by modulating several critical parameters of the carcinogenic process, such as genomic stability and local tumor cell invasion.
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PMID:Progression elevated gene-3 (PEG-3) induces pleiotropic effects on tumor progression: modulation of genomic stability and invasion. 1538 39

Chromosomal aneuploidy is associated with invasive bladder cancer and one of the genes implicated in these changes is Aurora-A/STK15/BTAK, that is localized on chromosome 20q13 and encodes a centrosome-associated serine/threonine kinase. To better understand the association between Aurora-A/STK15 expression, tumor aneuploidy and clinical prognosis, we sought to determine whether overexpression of Aurora-A/STK15 in cultured urothelial cells facilitated chromosomal instability. Using immunofluorescence staining, Northern and Western blot analyses, we verified that overexpression of Aurora-A/STK15 in bladder tumor cell lines enhanced chromosomal instability. Additionally, we observed that some bladder tumor cell lines expressed more Aurora-A/STK15 than cultured normal urothelial cells and that Aurora-A/STK15 expression was higher in an immortalized E7 urothelial cell line having 20q amplification than in an E6 line lacking 20q amplification. These results were consistent with our observations of higher mRNA levels in some T3 invasive bladder tumors than in T1 superficial tumors and adjacent normal bladder tissue. Overall our results suggest that overexpression of Aurora-A/STK15 in bladder tumor cells contributes to tumor progression by promoting chromosomal instability leading to aneuploidy.
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PMID:Aurora-A/STK15/BTAK enhances chromosomal instability in bladder cancer cells. 1554

Normal cells undergo anoikis when they lose adhesion to or encounter an inappropriate extracellular matrix. By contrast, oncogenic signaling in tumor cells enables resistance to anoikis, a trait that contributes to tumor progression. The B-RAF serine-threonine kinase is mutated in multiple cancers and functions as an oncogene in melanoma. Previously, we demonstrated that B-RAF and downstream mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling are necessary for protection from anoikis in mutant B-RAF-expressing melanoma cells. Regulation of Bcl-2 family members in melanoma and their role in B-RAF-mediated survival is poorly defined. Here, we provide evidence that B-RAF-MEK signaling protects against anoikis through alterations in two proapoptotic Bcl-2 family proteins: Bcl-xL/Bcl-2-associated death promoter (Bad) and Bcl-2-interacting mediator of cell death (Bim). B-RAF-MEK signaling regulates phosphorylation of the inhibitory serine-75 residue of Bad, and decreases Bad mRNA expression. RNA interference and overexpression experiments demonstrate that Bad contributes to the susceptibility of B-RAF-depleted cells to anoikis. Additionally, B-RAF-MEK signaling regulates the expression of Bim(EL), mainly through control of protein turnover. Increased Bim(EL) levels induce apoptosis in suspended cells and are required for anoikis in B-RAF-depleted cells. Depletion of Bim together with Bad has an additive effect on protecting B-RAF knockdown cells from anoikis. Together, our data show that Bad and Bim are major B-RAF responsive proteins regulating apoptosis in melanoma cells.
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PMID:Mutant B-RAF mediates resistance to anoikis via Bad and Bim. 1824 27

Aurora-A is a centrosome-associated serine/threonine kinase that is overexpressed in multiple types of human tumors. Primarily, Aurora-A functions in centrosome maturation and mitotic spindle assembly. Overexpression of Aurora-A induces centrosome amplification and G2/M cell cycle progression. Recently, it was observed that overexpression of Aurora-A renders cells resistant to cisplatin (CDDP)-, etoposide-, and paclitaxel-induced apoptosis. Our results indicate that already in initial stages of cancer progression Aurora-A overexpression could have a major role in inducing supernumerary centrosomes and aneuploidy, as shown by immunohistochemistry on tissue sections from various stages of human colon cancer. Aneuploidy was also observed after Aurora-A ectopic overexpression in colon cancer cells with MIN phenotype. Silencing of Aurora-A by RNA interference in tumor cell lines triggered arrest of the cell cycle associated to apoptosis/ mitotic catastrophe. Finally, Aurora-A transcriptional silencing seems to confer cancer cells a greater sensitivity to chemotherapy by vincristine, indicating Aurora-A as a possible gene target in cancer therapy.
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PMID:Aurora-A transcriptional silencing and vincristine treatment show a synergistic effect in human tumor cells. 1866 63

Centrosome amplification, which may accelerate tumor progression through chromosomal instability, is frequently observed in human malignancies. The intercellular relation between the number of centrosomes and chromosomes, however, is poorly understood. Therefore, the relationship between centrosomes and chromosomal copy number in the same cells was investigated in bladder cancer. Centrosomes were evaluated by immunohistochemistry, using anti-gamma-tubulin antibody in eight bladder cancer cell lines. Fluorescence in situ hybridization with centromeric probes for chromosomes 7, 9, and 17 was then performed on the same cells stained with gamma-tubulin. The number of centrosomes was directly proportional to the number of chromosomes in cells with centrosome amplification, while a large intercellular variation in chromosomal copy number was detected in cells with normal numbers of centrosomes. Cancer cells with centrosome amplification of even centrosome numbers had significantly more even numbers of chromosomes. In cancer cells with four centrosomes, even numbers of chromosomes were detected more frequently (87.5%). These bladder cancer cell lines showed Aurora-A and p53 overexpression. These data indicate the occurrence of centrosome amplification with the possible mechanism of cytokinesis failure, resulting in a doubling of the number of centrosomes and chromosomes.
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PMID:Intercellular centrosome number is correlated with the copy number of chromosomes in bladder cancer. 1938 7

Gastrointestinal stromal tumors (GISTs) generally harbor activating mutations in KIT or platelet-derived growth facter receptor (PDGFRA). Mutations in these receptor tyrosine kinases lead to dysregulation of downstream signaling pathways that contribute to GIST pathogenesis. GISTs with KIT or PDGFRA mutations also undergo secondary cytogenetic alterations that may indicate the involvement of additional genes important in tumor progression. Approximately 10-15% of adult and 85% of pediatric GISTs do not have mutations in KIT or in PDGFRA. Most mutant adult GISTs display large-scale genomic alterations, but little is known about the mutation-negative tumors. Using genome-wide DNA arrays, we investigated genomic imbalances in a set of 31 GISTs, including 10 KIT/PDGFRA mutation-negative tumors from nine adults and one pediatric case and 21 mutant tumors. Although all 21 mutant GISTs exhibited multiple copy number aberrations, notably losses, eight of the 10 KIT/PDGFRA mutation-negative GISTs exhibited few or no genomic alterations. One KIT/PDGFRA mutation-negative tumor exhibiting numerous genomic changes was found to harbor an alternate activating mutation, in the serine-threonine kinase BRAF. The only other mutation-negative GIST with significant chromosomal imbalances was a recurrent metastatic tumor found to harbor a homozygous deletion in chromosome arm 9p. Similar findings in several KIT-mutant GISTs identified a minimal overlapping region of deletion of approximately 0.28 Mbp in 9p21.3 that includes only the CDKN2A/2B genes, which encode inhibitors of cell-cycle kinases. These results suggest that GISTs without activating kinase mutations, whether pediatric or adult, generally exhibit a much lower level of cytogenetic progression than that observed in mutant GISTs.
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PMID:High density DNA array analysis reveals distinct genomic profiles in a subset of gastrointestinal stromal tumors. 1958 85

The mitotic kinase Aurora-A (Aur-A) is required to form the bipolar spindle and ensure accurate chromosome segregation before cell division. Aur-A dysregulation represents an oncogenic event that promotes tumor formation. Here, we report that Aur-A promotes breast cancer metastasis. Aur-A overexpression enhanced mammary cell migration by dephosphorylation and activation of cofilin, which facilitates actin reorganization and polymerization. Cofilin knockdown impaired Aur-A-driven cell migration and protrusion of the cell membrane. Conversely, overexpression of activated cofilin abrogated the effects of Aur-A knockdown on cell migration. Moreover, Aur-A overexpession increased the expression of the cofilin phosphatase Slingshot-1 (SSH1), contributing to cofilin activation and cell migration. We found that phosphatidylinositol 3-kinase (PI3K) inhibition blocked Aur-A-induced cofilin dephosphorylation, actin reorganization, and cell migration, suggesting crosstalk with PI3K signaling and a potential benefit of PI3K inhibition in tumors with deregulated Aur-A. Additionally, we found an association between Aur-A overexpression and cofilin activity in breast cancer tissues. Our findings indicate that activation of the cofilin-F-actin pathway contributes to tumor cell migration and metastasis enhanced by Aur-A, revealing a novel function for mitotic Aur-A kinase in tumor progression.
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PMID:The mitotic kinase Aurora-A induces mammary cell migration and breast cancer metastasis by activating the Cofilin-F-actin pathway. 2104 47

Aurora B is a serine-threonine kinase belonging to the highly conserved Aurora family of mitotic kinases. Aurora B is a chromosomal passenger protein involved in chromosome segregation, spindle-checkpoint, and cytokinesis. Alteration of each of these steps could induce aneuploidy, one of main features, and driving force of cancer progression. The overexpression of Aurora B has been observed in several tumor types, and has been linked with a poor prognosis of cancer patients. In this review we will focus on the role of Aurora B in cancer development, its role as a prognostic marker, and the clinical outcome of recently developed Aurora(s) inhibitors.
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PMID:Aurora B: a new prognostic marker and therapeutic target in cancer. 2114 15


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