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)

CD82 (KAI1) and CD63 (ME491) are highly glycosylated proteins which belong to the transmembrane 4 superfamily (TM4SF). CD82 has been implicated as a possible prostate cancer metastasis suppressor gene, whereas CD63 is involved in the progression of human melanoma cancer. Down-regulation of both CD82 and CD63 expression has been associated with the metastatic potential of several solid tumors. Currently, information is lacking on the role of CD82 and CD63 during thyroid carcinogenesis. The aim of this study was to determine whether the expression of CD82 and CD63 is a useful prognostic indicator in patients with thyroid carcinoma. The expression of CD82 and CD63 was analysed by reverse transcriptase-PCR (RT-PCR) and immunohistochemistry in benign goiter (n=12) and 75 primary thyroid carcinoma tissue specimens (PTC: 33, FTC: 24, UTC: 18) out of which 36 were non-metastasized primary tumors and 39 were metastasized tumors (regional lymph node and/or distant metastases). All of the benign goiter tissues showed CD82 expression. By contrast, a significant decrease in CD82 mRNA and protein levels was detected in carcinoma tissues as compared to benign goiter tissues (p<0.001). A similar down-regulation was observed in metastasized tumor tissues when compared with non-metastasized tumors (all p<0.05). CD82 expression was correlated with pTNM status of differentiated and undifferentiated thyroid tumor and the pathologic stage of differentiated thyroid tumor. In contrast to CD82, CD63 mRNA and protein expression was unchanged in all thyroid carcinomas. Benign goiter tissues showed weak expression of CD63. There were no significant correlation between CD63 mRNA/protein expression and any clinical/pathological parameters. Our results support the hypothesis that down-regulation of CD82 expression may reflect an increased in vivo metastatic potential of thyroid cancer cells. CD82 may serve as a prognostic marker of metastasis in thyroid cancer. Constitutive expression of CD63 may indicate that this factor does not play a direct role in thyroid carcinogenesis.
Int J Mol Med 2004 Oct
PMID:CD82, and CD63 in thyroid cancer. 1537 77

The RET/PTC3 oncogene is a genetically rearranged and constitutively activated tyrosine kinase receptor that is common in papillary thyroid cancer. Because RET/PTC3 is chronically overexpressed in these thyroid cancer cells, and RET/PTC3-expressing tumors are associated with overactivity of tyrosine kinase signaling pathways and a more aggressive clinical course, we questioned whether chronic RET/PTC3 expression enhances cellular responses to thyroid mitogens in vitro. We stably transfected FRTL-5 cells with the RET/PTC3 gene; transfected and control cell lines were cultured without insulin, TSH, or serum. Thymidine incorporation into DNA was enhanced in the RET/PTC3 cells, but transformation was not observed. RET/PTC3 cells demonstrated higher basal and insulin-stimulated levels of activated Akt, both of which were reduced by LY294002, a PI3 kinase inhibitor, but not PD98059, a MEK inhibitor. By contrast, mitogen activated protein kinase (MAP kinase) was only minimally activated in RET/PTC3 cells before and after stimulation. Consistent with preferential activation of PI3 kinase, increased levels of total and phosphorylated IRS2 protein, relative activation of PDK-1, and enhanced IRS2-p85 interactions were identified in RET/PTC3-expressing cells. RET/PTC3 cells were also sensitized to insulin-induced thymidine incorporation; this effect was blocked by PI3 kinase (LY294002) rather than MEK 1/2 (PD98059) inhibitors. In summary, we have demonstrated that RET/PTC3 expression enhances basal and insulin-stimulated DNA synthesis through PI3 kinase, cooperatively activates Akt with insulin via PI3 kinase, and preferentially activates the Akt rather than MAP kinase pathway in FRTL-5 cells.
Mol Carcinog 2004 Oct
PMID:Chronic expression of RET/PTC 3 enhances basal and insulin-stimulated PI3 kinase/AKT signaling and increases IRS-2 expression in FRTL-5 thyroid cells. 1537 48

Activating mutations in RAS protooncogenes are associated with several different histotypes of thyroid cancer, including anaplastic thyroid carcinoma. The latter is the most aggressive cancer of the thyroid gland, showing little or no expression of the differentiated phenotype. Likewise, expression of viral RAS oncogenes in FRTL-5 rat thyroid cells mimics such loss of differentiation. We established FRTL-5 cell lines stably expressing constitutively active forms of RAS, either of viral (v-Ha-RAS or v-Ki-RAS) or cellular (H-RAS(V12)) origin and generated a tamoxifen-inducible RAS oncoprotein to analyze the timing of RAS effects on thyroid differentiation. In RAS-transformed FRTL-5 cells, we measured the expression of many thyroid-specific genes by real-time PCR and observed that a clear loss of differentiation was only obtained in the presence of high RAS oncogene expression. In contrast, TSH-independent growth appeared to be induced in the presence of both low and high levels of oncogenic RAS expression. We also showed that inhibition of differentiation is an early RAS-induced phenomenon. Finally, we demonstrated that only high doses of RAS oncogenes are able to inhibit the activity of Titf1 and Pax8, two transcription factors essential for the maintenance of thyroid differentiation, and that the homeodomain of Titf1 is a target of the inhibitory action of RAS. Our results represent the first evidence of a dose-dependent effect of RAS oncogenes on thyroid epithelial differentiation.
Mol Endocrinol 2005 Jan
PMID:Dose-dependent inhibition of thyroid differentiation by RAS oncogenes. 1538 94

We previously demonstrated that the human nicotinamide N-methytransferase (NNMT) gene was highly expressed in many papillary thyroid cancers and cell lines. The expression in other papillary and follicular cancers or cell lines and normal thyroid cells was low or undetectable. To gain an understanding of the molecular mechanism of this cell-specific expression, the NNMT promoter was cloned and studied by luciferase reporter gene assay. The promoter construct was expressed highly in papillary cancer cell lines, including those with higher (e.g. BHP 2-7) and lower (e.g. BHP 14-9) NNMT gene expression, and expressed weakly in follicular thyroid cancer cell lines. Further study with 5'-deletion promoter construct suggested that the NNMT promoter was regulated differently in BHP 2-7 and BHP 14-9 cells. In BHP 2-7 cells, promoter activity was dependent on an upstream sequence. In BHP 14-9 cells, sequence in the basal promoter region contributed notably to the overall promoter activity. RT-PCR or Western blot analysis indicated that hepatocyte nuclear factor-1beta (HNF-1beta) was expressed in only papillary cancer cell lines with high NNMT gene expression. HNF-1beta was not expressed or expressed very weakly in other papillary, follicular, and Hurthle cancer cell lines and primary cultures of normal thyroid cells and benign thyroid conditions. A HNF-1 binding site was identified in the NNMT basal promoter region. Mutations in this site decreased NNMT promoter activity in the HNF-1beta-positive BHP 2-7 cells, but not in the HNF-1beta-negative BHP 14-9 cells. HNF-1beta bound to the HNF-1 site specifically as a homodimer as determined by gel retardation assays with HNF-1beta-specific antibody. Cotransfection of a HNF-1beta expression plasmid increased NNMT promoter activity significantly in both HNF-1beta-positive and -negative thyroid cancer cell lines and Hep G2 liver cancer cells. Furthermore, transient expression of HNF-1beta in BHP 14-9 cells increased endogenous NNMT protein levels. In summary, HNF-1beta functions as a transcription activator for NNMT gene expression in some papillary thyroid cancer cells.
Mol Endocrinol 2005 Feb
PMID:Activation of nicotinamide N-methyltransferase gene promoter by hepatocyte nuclear factor-1beta in human papillary thyroid cancer cells. 1548 44

RET is the receptor for glial-derived neurotrophic factor growth factors. It is a paradigm of a single gene that causes different types of human cancer when targeted by different genetic alterations. Like other receptor tyrosine kinases, once activated, RET recruits a variety of signaling molecules that mediate biological responses. Here we review data on the signaling pathways that lead to RET-mediated cell transformation and recent evidence that manipulation of RET holds promise for thyroid cancer treatment.
Cell Mol Life Sci 2004 Dec
PMID:Dysfunction of the RET receptor in human cancer. 1558 57

Despite the uncontested role of p53 in cycle arrest/cell death after cisplatin treatment, to date the question whether wild-type p53 confers a resistant or sensitive status on the cell is still a matter of debate. Isogenic and isophenotypic human thyroid papillary carcinoma cell line variants for p53 differently expressed cycle genes after cisplatin treatment. Seven genes (CDC6-related protein, CCNC, GAS1, TFDP2, MAPK10/JNK3, WEE1, RPA1) selected after expression on an Atlas human cell cycle array were analyzed by quantitative real-time PCR. While cisplatin treatment increased their expression in p53 wild-type cells it decreased it in cells with inactivated p53 and had no or less effect on cells with mutated p53. These results show that in a well-defined system, different alterations of p53 can lead to a different regulation of genes and hence to either resistance or sensitivity to cisplatin. Moreover for the first time, MAPK10/JNK3 was identified in human thyroid cells and tissue. Four of the genes (CDC6-related protein, CCNC, GAS1 and TFDP2) were decreased in human papillary carcinoma tissues. Relevance of these genes (especially a decrease in GAS1 in thyroid papillary carcinoma) in various malignant pathologies has already been shown. These genes may be explored as new markers in advanced thyroid cancer such as metastatic and anaplastic forms displaying p53 alterations.
Cell Mol Life Sci 2005 Jan
PMID:Cisplatin-induced genes as potential markers for thyroid cancer. 1561 7

We have previously reported that the hormonal form of 1alpha,25-dihydroxyvitamin D3 (1,25-VD3), and its noncalciomimetic analog EB1089, arrest the growth of human thyroid cancer cells by increasing the cell cycle inhibitor p27. In the present study, we investigated whether the tumor-suppressive effects of vitamin D (VD) compounds may also be mediated by mechanisms that govern cell adhesiveness. Both 1,25-VD3 and EB1089 increased cell adhesiveness, an effect that was accompanied by consistent increases in fibronectin (FN) expression. Introduction of small interfering RNA against FN resulted in down-regulation of FN expression and diminished cell adhesiveness to a collagen-type I matrix. To determine whether this action of 1,25-VD3 was mediated through the PTEN/phosphoinositol 3-kinase pathway, we examined whether this tumor suppressor protein/dual phosphatase can influence FN expression and consequently cell adhesiveness Overexpression of wild-type PTEN induced FN expression as well as cell adhesiveness. In contrast, introduction of mutant forms of PTEN failed to induce FN and led to diminished cell adhesiveness. Conversely, small interfering RNA-mediated PTEN down-regulation attenuated FN expression as well as cell adhesiveness. The attenuated FN expression was also associated with relative insensitivity to 1,25-VD3 growth-suppressive action. Cells down-regulated for FN demonstrated a more aggressive growth pattern in xenografted mice and were also relatively insensitive to 1,25-VD3 treatment. Taken together, our findings highlight the significance of FN in modulating thyroid cancer cell adhesiveness and, at least in part, in mediating VD actions on neoplastic cell growth.
Mol Endocrinol 2005 Sep
PMID:1alpha,25-Dihydroxyvitamin D3 targets PTEN-dependent fibronectin expression to restore thyroid cancer cell adhesiveness. 1589 Jun 70

Single photon emission tomography (SPET) represents an indispensable diagnostic tool in nuclear medicine. Due to better contrast resolution, cross sectional and 3D images, SPET plays a useful complementary tool to bidimensional planar scintigraphy in certain clinical conditions, while representing the procedure of choice in others. However, high resolution SPET with pinhole collimator (P-SPET) can improve conventional SPET sensitivity with parallel hole collimators. This review summarizes data on the employment of conventional SPET and P-SPET in breast cancer, differentiated thyroid cancer (DTC) and hyperparathyroidism patients, using the cationic lipophilic complexes [(99m)Tc]metoxy isobutyl isonitrile (sestaMIBI) and [(99m)Tc]tetrofosmin as oncotropic radiotracers. In breast cancer patients, SPET with these radiotracers can play an important complementary role to planar scintimammography in detecting primary tumors, especially when non palpable and small in size, whereas SPET and particularly P-SPET represents the procedure of choice in preoperative axillary lymph node status evaluation in which planar is almost always irrelevant. In DTC follow-up patients, SPET and P-SPET with cationic lipophilic radiotracers are indicated in both locoregional and distant metastasis detection, especially in patients with high Tg serum levels and negative radioiodine scanning in whom these procedures represent a reliable alternative to diagnostic (131)I scanning. Moreover, the combined use of [(99m)Tc]tetrofosmin P-SPET and US can identify recurrences and lymph node metastases in the neck, both fixing and non fixing iodine, downstaged or negative at (131)I scanning. SPET can also be a useful complementary tool to planar parathyroid scintigraphy in the detection and localization of small and ectopic parathyroid adenomas in the neck or mediastinum, while neck P-SPET seems to also significantly increase planar sensitivity in hyperplastic glands. SPET and P-SPET are indicated in persistent and recurrent hyperparathyroidism including from carcinoma.
Q J Nucl Med Mol Imaging 2005 Jun
PMID:99mTc labelled cationic lipophilic complexes in malignant and benign tumors: the role of SPET and pinhole-SPET in breast cancer, differentiated thyroid carcinoma and hyperparathyroidism. 1601 Feb 52

Papillary thyroid carcinoma is the most common malignancy of the thyroid. It is a well-differentiated tumor and the majority behaves in an indolent fashion. The pathologic diagnosis of papillary carcinoma in both cytology and histologic specimens is based upon demonstration of typical nuclear morphology. Using these morphologic criteria, most papillary cancers can be diagnosed with ease, except cases in which there is a paucity of diagnostic nuclear features. Despite advances in the treatment of thyroid cancer, disease recurrences and metastasis can be observed in 20% of cases. Recently, many advances have been made in the pathogenesis of papillary thyroid carcinoma. The notable genetic events include Ret/PTC rearrangements, Ras and BRAF gene mutations. The identification of these has also led to their use in diagnosis and predicting prognosis of papillary thyroid carcinoma. In addition, these involved genes may also serve as targets for cancer chemotherapy in patients where standard thyroid cancer treatment is not effective.
Expert Rev Mol Diagn 2005 Jul
PMID:Pathologic diagnosis of papillary thyroid carcinoma: today and tomorrow. 1601 75

Coordination of events leading to differentiation is mediated by the concerted action of multiple signal transduction pathways. In general, the uncoupling of mechanisms linking differentiation to cell cycle exit is a hallmark of cancer, yet the identity and regulation of molecules integrating signal transduction pathways remains largely unknown. One notable exception is DARPP-32 (dopamine and cAMP-regulated neuronal phosphoprotein, molecular mass, 32 kDa), a third messenger that integrates multiple signaling pathways in the brain. Thyroid cells represent an excellent model for understanding the coupling of signal transduction pathways leading to both proliferation and differentiation. The cooperative action of IGF-I and TSH together, but not alone, enable thyroid cells to proliferate while maintaining their differentiated state. How signaling downstream from these molecules is integrated is not known. Here we show that DARPP-32 expression is targeted by TSH and IGF-I in thyrocytes. Significantly, dedifferentiated, tumoral, or Ras-transformed thyrocytes fail to express DARPP-32 whereas short interfering RNA-mediated silencing of DARPP-32 expression in normally differentiated thyroid cells results in loss of differentiation markers such as thyroid transcription factor 1, Pax8, thyroglobulin, and the Na/I symporter. Consistently, DARPP-32 reexpression in ras-transformed cells results in reactivation of the otherwise silent thyroglobulin and thyroperoxidase promoter. Thus, DARPP-32 is critical for the maintenance of thyroid differentiation by TSH and IGF-I, and loss of DARPP-32 expression may be a characteristic of thyroid cancer. Our results also raise the possibility that DARPP-32 may play a similar role in the maintenance of differentiation of a range of other cell types.
Mol Endocrinol 2005 Dec
PMID:DARPP-32 (dopamine and 3',5'-cyclic adenosine monophosphate-regulated neuronal phosphoprotein) is essential for the maintenance of thyroid differentiation. 1602 Apr 82


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