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 determine which genes may be regulated by Akt and participate in the transformation of cells, we have examined by microarray analyses genes turned on in the prostate cancer cell line, PC3, when Akt activity was induced. PC3 cells, which lack the lipid phosphatase PTEN, were treated overnight with a reversible inhibitor of the phosphatidylinositol 3-kinase, LY294002 (a treatment which was found to reversibly decrease Akt enzymatic activity). The inhibitor was then washed out and mRNA collected 2, 6, and 10 h later and compared by microarray analyses with mRNAs present immediately after removal of the inhibitor. One of the identified induced mRNAs, Fra-1, was further studied by transient transfections of a reporter construct containing its 5' regulatory region. This construct was found to be directly induced 4- to 5-fold by co-transfection with constitutively active Akt3 but not kinase dead Akt. The regulation by Akt3 was found to be due to two specific regions in the Fra-1 regulatory sequence which match Sp1 consensus sites. Finally, gel shift studies showed that the binding of Sp1 to one of these sites was dependent on the PI 3-kinase pathway. These results indicate that LY294002 treatment and washout is a useful method to study the activation of Akt in the context of a tumor cell. Moreover, the identification of Fra-1 as an Akt-regulated gene may have implications for the ability of Akt to transform cells since Fra-1 has been implicated in cell growth and the aggressiveness of tumors.
Mol Cancer Res 2003 Apr
PMID:Gene expression profiling in prostate cancer cells with Akt activation reveals Fra-1 as an Akt-inducible gene. 1269 67

Highly aggressive, rapidly growing tumors are exposed to hypoxia or even anoxia which occurs as a consequence of inadequate blood supply. Both hypoxia and consecutive hypoxia/reoxygenation exert a variety of influences on tumor cell biology. Among these are activation of certain signal transduction pathways and gene regulatory mechanisms, induction of selection processes for gene mutations, tumor cell apoptosis and tumor angiogenesis. Most of these mechanisms contribute to tumor progression. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. In this review, we summarize the current knowledge about the molecular mechanisms induced by tumor cell hypoxia with a special emphasis on intracellular signal transduction, gene regulation, angiogenesis and apoptosis. Interfering with these pathways might open perspectives for future innovative treatment of highly aggressive metastasizing tumors.
Mol Cancer 2003 Apr 17
PMID:Molecular responses to hypoxia in tumor cells. 1274 39

Multiple studies using primary tumors have reported that alterations in p53 expression and detection of TP53 mutations are associated with clinical aggressiveness and poor response to specific therapies. However, there is no general agreement regarding the optimal technical approach to the analysis of p53. We have studied a series of 100 primary colorectal adenocarcinomas by immunohistochemistry with the monoclonal antibody PAb1801, and single-stranded conformation polymorphism (PCR-SSCP, exons 4-8) followed by direct sequencing of shifted bands. p53 Nuclear staining was undetectable (score 0) in 29 of 100 cases. However, gene mutations were detected in 15 of these cases, with all of these mutations leading to abnormal proteins. p53 Nuclear staining was detectable and scored as less than 10% tumor cells positive in 15 of 100 cases but was still considered to be displaying a p53-negative phenotype because the cut-off value for positivity was 10% positive tumor cells. Nevertheless, TP53 gene mutations were detected in 2 of these cases. p53 Nuclear immunoreactivities were detectable and scored as more than 10% tumor cells positive in 56 cases, considered the p53-positive phenotype. TP53 gene mutations were identified in 51 of these 56 cases. These results reveal that immunohistochemical assessment does not predict TP53 mutation status in colorectal adenocarcinoma, mainly in cases displaying absence of nuclear staining. It is thus concluded that molecular profiling should be conducted in parallel with immunophenotyping when analyzing colorectal tumors for p53 status.
Appl Immunohistochem Mol Morphol 2003 Jun
PMID:Lack of p53 nuclear immunostaining is not indicative of absence of TP53 gene mutations in colorectal adenocarcinomas. 1277 96

The purpose of this study was to investigate comparatively the chronological changes of age-adjusted incidence rate (AAIR) as well as age-specific incidence rate (ASIR) of cancers of the breast (Br), the uterine cervix (Cer) and the stomach (St) from early 1960s to mid 1980s (5 data collections) using the data sets of 9 female populations world wide, the total data set number amounting to 45 per tumor. More specifically, we wanted to see whether or not there was any regular relationship between the differential time trends of the above 3 human neoplasias and their oncogene-tumor suppressor gene balances. Our investigation proceeded in 3 steps as follows: step 1, straight line regression analysis of log AAIR was applied to each of tumor pairs Br(x)-Cer(y), Br(x)-St(y) and Cer(x)-St(y). Step 2, direct successive elimination test (Gauss) of log AAIR was applied to each of 6 tumor pairs (Br-St, Br-Cer, Cer-St, Cer-Br, St-Br and St-Cer) to assess the fitness of a test tumor (x-partaner of fitness test) to either the oncogene type equilibrium model (r=-1.000) or the tumor suppressor gene type equilibrium model (r=+1.000). For each of 6 tumor pairs, the fitness test was repeated 3 times using i) the original data set in the ordinary (x,y) framework, ii) the rect-type data sets in the rect-(x,y) framework, and iii) the para-type data set in the para-(x,y) framework. The fitness of a test tumor (x partner in the calculation) to an equilibrium system was assessed in terms of the correlation coefficient value r within the range of -1.000 to +1.000 (step 3). Staging of the whole carcinogenesis process was attempted for each of 3 human neoplasias using either the ASIR profiles of a high- and low-risk populations, and/or those of early 1960s and mid 1980s. Results of key importance are given as follows: i) Br with rapidly growing cancer risk, Cer with rapidly declining cancer risk and St with slowly declining cancer risk were clearly distinguished from one another by the single regression analysis. ii) The fitness test demonstrated that Br, Cer and St each were found to have one score in the positivity test of oncogene activation (r=-1.000), whereas Br with 4 scores, Cer with 2 scores and St with 3 scores of tumor suppressor gene inactivation (r=+1.000) were found to have differential openness to the fitness test of Gauss for the detection of tumor suppressor gene inactivation. It is indicated that the differential opennesses of a window to tumor suppressor gene inactivation observed in 3 human neoplasias represent a measure of the time-linked aggressiveness of cancer risk. iii) The comparison of 4 ASIR profiles of Br suggested the presence of 3 stages of carcinogenesis progression, of which the 1st stage was tentatively classified as of heredity-dependent origin, and the 2nd and the 3rd stages were classified as of environment-dependent origin. The St ASIR profile represents a fusion product of very minor heredity-dependent stage I and a major environment-dependent stage II. In contrast, the Cer ASIR profile completely lacked a heredity-dependent stage. The integrity of the above findings is discussed in the light of a number of pioneering achievements along the line of the steroid criminal theory of carcinogenesis in humans and in non-human mammals.
Int J Mol Med 2003 Sep
PMID:Parallel comparison of chronological risk changes among cancers of the breast, the uterine cervix and the stomach, as tested in 9 female populations of the world from early 1960s to mid 1980s: a stochastic study. 1288 54

The E2F transcription factors are key downstream targets of the retinoblastoma protein (pRB) tumor suppressor. We have previously shown that E2F3 plays a critical role in mediating the mitogen-induced activation of E2F-responsive genes and contributes to both the inappropriate proliferation and the p53-dependent apoptosis that arise in pRB-deficient embryos. Here we show that E2F3 also has a significant effect on the phenotype of tumor-prone Rb(+/-) mice. The absence of E2F3 results in a significant expansion in the life spans of these animals that correlates with a dramatic alteration in the tumor spectrum. E2F3 loss suppresses the development of the pituitary tumors that normally account for the death of Rb(+/-) mice. However, it also promotes the development of medullary thyroid carcinomas yielding metastases at a high frequency. This increased aggressiveness does not seem to result from any change in p53 levels or activity in these tumors. We show that, instead, E2F3 loss leads to an increase in the rate of tumor initiation. Finally, analysis of Rb(+/-); E2f3(+/-) mice shows that this tumor-suppressive function of E2F3 is dose dependent.
Mol Cell Biol 2003 Sep
PMID:E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas. 1294 80

Osteopontin (OPN) is a secreted phosphoprotein that has been associated with malignancy of breast and other cancers. OPN binds to several cell surface integrins including alpha(v)beta(3), alpha(v)beta(5), and alpha(v)beta(1). Although the relative contribution of these integrins to breast cancer cell malignancy is uncertain, correlative studies suggest that alpha(v)beta(3) may be particularly associated with increased tumor aggressiveness. Previously, we reported that tumorigenic, nonmetastatic 21NT mammary carcinoma cells respond to OPN through alpha(v)beta(5) and alpha(v)beta(1) but not alpha(v)beta(3). Here, we determined that 21NT cells lack beta(3) expression, and we asked whether expression of alpha(v)beta(3) could enhance the ability of breast cancer cells to respond to the malignancy-promoting effects of OPN both in vitro and in vivo. 21NT cells stably transfected with beta(3) showed significantly increased adhesion, migration, and invasion to OPN in vitro compared with vector control. To determine if beta(3) could also enhance the response of breast epithelial cells to OPN in vivo, cells stably transfected with both beta(3) and OPN (NT/Obeta(3)) were injected into the mammary fat pad of female nude mice and primary tumor growth was assessed relative to controls. Mice injected with NT/Obeta(3) cells demonstrated a significantly increased primary tumor take (75% of mice) compared with controls (0-12.5% of mice) as well as a decreased tumor doubling time and a decreased tumor latency period. These results suggest that increased expression of the alpha(v)beta(3) integrin during breast cancer progression can make tumor cells more responsive to malignancy-promoting ligands such as OPN and result in increased tumor cell aggressiveness.
Mol Cancer Res 2003 Sep
PMID:Beta(3) integrin expression increases breast carcinoma cell responsiveness to the malignancy-enhancing effects of osteopontin. 1451 43

Recently carbon-11 acetate (AC) positron emission tomography (PET) has been reported to be of clinical value for the diagnosis of cancer that is negative on fluorine-18 fluorodeoxyglucoce (FDG) PET. We investigated the uptake of AC in lung cancer to determine whether this tracer is of potential value for tumour detection and characterisation, and to compare AC PET imaging with FDG PET and technetium-99m sestamibi (MIBI) single-photon emission tomography (SPET). Twenty-three patients with 25 lung cancers underwent AC and FDG PET. Twenty of 23 patients were also investigated with MIBI SPET. Dynamic images were acquired for 26 min after the injection of 555 MBq of AC. Standardised uptake values (SUVs) and/or tumour to non-tumour activity ratios (T/N) for each tumour were investigated at 10-20 min after AC administration, 40-60 min after administration of 185 MBq FDG and 15-45 min after administration of 555 MBq MIBI. Twenty lung cancers were resected surgically, and the degree of tracer uptake in the primary lesion was correlated with histopathological features (cell dedifferentiation and aggressiveness) and prognosis. Rapid uptake of AC followed by extremely slow clearance was observed. For the purpose of tumour identification, AC PET was inferior to FDG PET in 8 of 25 (32%) lung cancers, and the T/N of AC was lower than that of FDG. However, AC PET was superior to FDG PET in the identification of a slow-growing tumour (bronchiolo-alveolar carcinoma). There was a positive correlation between AC uptake (T/N) and MIBI uptake (T/N) (r=0.799, P<0.0001). A positive correlation was not observed between either AC or MIBI uptake and the degree of cell dedifferentiation in lung adenocarcinomas, whereas FDG uptake did correlate with the degree of cell dedifferentiation. In lung adenocarcinoma, there was a weak correlation between aggressiveness and FDG uptake, but no correlation was evident for AC and MIBI. In addition, a positive correlation was not observed between AC or MIBI uptake and postoperative recurrence in lung adenocarcinoma, whereas FDG uptake did correlate with postoperative recurrence. Thus, the greater the FDG uptake, the higher the malignant grade. In conclusion, for the purpose of tumour identification, AC PET was inferior to FDG PET but superior to MIBI SPET. Neither AC nor MIBI uptake reflects the malignant grade in lung adenocarcinoma, whereas FDG uptake does. AC PET is less diagnostically informative than FDG PET in patients with lung cancer. However, AC PET may play a complementary role in the identification of low-grade malignancies that are not FDG avid.
Eur J Nucl Med Mol Imaging 2004 Jan
PMID:11C-acetate PET imaging of lung cancer: comparison with 18F-FDG PET and 99mTc-MIBI SPET. 1457 13

Multiple endocrine neoplasia Type 2 is a rare familial cancer syndrome transmitted in an autosomal dominant manner. It is characterized by the association of medullary thyroid carcinoma with pheochromocytoma and hyperparathyroidism. Medullary thyroid carcinoma, present in virtually all patients, is the principal cause of death. In 1993, germline mutations in the RET proto-oncogene were identified as the underlying cause of the syndrome. Genetic screening of at-risk family members can now be performed with high specificity and sensitivity. The ability to determine gene carrier status at a preclinical stage is of great value as it allows early prophylactic thyroidectomy. The specific RET codon mutation correlates with clinical variants of the syndrome, age at onset and aggressiveness of medullary thyroid carcinoma. This review will focus on mutational spectrum, genotype-phenotype correlations and clinical decisions based on genetic information.
Expert Rev Mol Diagn 2003 Nov
PMID:Molecular diagnosis of multiple endocrine neoplasia Type 2. 1462 4

The aim of this study was to investigate telomerase reactivation, to quantitatively measure the human telomerase reverse transcriptase (hTERT) content and telomerase activity level (TA) in routine histological and cytological samples, and to examine the relationship between these values and morphological factors. We analyzed 86 (35 cytological and 51 histological) lesions which were divided into four main groups: renal tumors, soft tissue tumors, bladder-urine and thyroid gland lesions. The relative expression of mRNA of hTERT was examined by real-time polymerase chain reaction (RT-PCR). Almost all of the renal cell carcinomas showed TA. In soft tissue tumors no correlation was seen between TA and histogenesis, aggressiveness and prognosis. Concerning cytological material a very good correlation was seen between TA and the benign or malignant nature of these tumors (92.3% specificity and 60% sensitivity). Our results indicated that TA can be used beside histology also in cytologic samples, for example in the preoperative differential diagnosis of the thyroid gland lesions and urine samples. Telomerase reactivation may not play an important role in tumorigenesis in STT. Useful observations can be made by concentrating not only on one group of diseases or localization but the unselected analysis of routine diagnostic cases can also be of help both in diagnosis and therapy.
Int J Mol Med 2004 Feb
PMID:Measuring telomerase activity in various human tumors in routine histology and cytology. 1471 39

Prostate cancer is the most frequent cancer among men in most developed countries, yet little is known about its causes. Older age, African ancestry and a positive family history of prostate cancer have long been recognized as important risk factors. The evidence that genetics probably plays a critical role is based on a variety of study designs, including case-control, cohort, twin and family-based, all of which are reviewed in detail. The search for prostate cancer susceptibility genes by linkage studies offered early hope that finding genes would be as 'easy' as finding genes for breast cancer and colon cancer susceptibilities. However, this hope has been dampened by the difficulty of replicating promising regions of linkage. This review provides updates on recent developments, and a broad view of the disparate findings from different linkage studies. Early linkage results have provided targeted candidate regions for prostate cancer susceptibility loci, including HPC1 on chromosome 1q23-25, PCAP on chromosome 1q42-43, CAPB on chromosome 1p36, linkage to chromosome 8p22-23, HPC2 on chromosome 17p, HPC20 on chromosome 20q13, and HPCX on chromosome Xq27-28. These linkage findings lead to refined mapping and mutation screening of several strong candidate genes, including ELAC2, RNASEL and MSR1. Up to now, a total of 10 genome-wide linkage scans for prostate cancer susceptibility have been completed, and are reviewed. Furthermore, recent findings that Gleason's grade, a measure of aggressiveness of prostate cancer, is linked to several genomic regions are reviewed. Finally, the roles of environmental and dietary risk factors, and common genetic polymorphisms of genes likely to play a role in common forms of prostate cancer, are briefly discussed within in the context of searching for genes that influence prostate cancer risk.
Hum Mol Genet 2004 Apr 01
PMID:The complex genetic epidemiology of prostate cancer. 1474 51


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