Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Forty-seven samples of paraffin-embedded formalin-fixed (and 25 related frozen) sections of 27 primary pleomorphic adenomas, 15 recurrent pleomorphic adenomas and 5 carcinomas in pleomorphic adenomas were studied to analyse their immunohistologic patterns with respect to the ratio of the expression of 'normally' and 'aberrantly' differentiated cell types. In primary pleomorphic adenoma PTHrP-positive cells are seen in the inner layer of tubulo-ductal structures, in part of the cells in the mucoid, chondroid, or myxochondroid matrix, and in the squamous metaplastic areas. Bcl-2-positive cells are found in the outer layer of tubulo-ductal structures, in part of the cells in the mucoid, chondroid, or myxochondroid matrix, and around the squamous metaplastic areas. In one case of primary pleomorphic adenoma, which recurred later, the positivity for Bcl-2 is more intense and seen in the periphery of this tumour with a predominantly myxoid pattern. In recurrent pleomorphic adenomas, which also mostly showed a predominantly myxoid pattern, the positivity for Bcl-2 showed a pattern similar to the primary-to-recur tumour. PTHrP-positive cells are found less frequently than Bcl-2-positive cells. In carcinoma in pleomorphic adenoma, the benign part shows the features of primary pleomorphic adenoma with its Bcl-2 and PTHrP-positivity patterns. The malignant part strongly shows Bcl-2-positive cells in the periphery of the tumour. We conclude that the maintained presence of Bcl-2 and PTHrP-positive cells in the tumours we studied shows the variable capacity of tumour cells to differentiate.
 ...
PMID:Immunohistochemical pattern of Bcl-2- and PTHrP-positive cells in primary, in recurrent and in carcinoma in pleomorphic adenomas. 892 64

Parathyroid hormone-related protein (PTHrP) was first identified as a pathogenetic factor for the hypercalcemia of malignancy. Recently PTHrP is focused as a physiological paracrine factor regulating cell proliferation and differentiation in many tissues during fetal and postnatal growth. Evidence for the skeletal origin of PTHrP comes from several sources and targeted disruption of the PTHrP gene in mice has resulted in a phenotype with accelerated endochondral bone formation, suggesting PTHrP as a factor regulating chondrocyte differentiation. Indian hedgehog, one of the conserved family of hedgehog regulating segmentation of Drosophila, is found to be an upstream factor of PTHrP in a regulating pathway of chondrocyte differentiation. Moreover, Bcl-2, a protein that controls programmed cell death in several cell types, is suggested to lie downstream of PTHrP in this pathway. A point mutation of PTH/PTHrP receptor is identified in a patient with Jansen-type metaphyseal chondrodysplasia and constitutive, ligand independent activation is indicated in this mutant receptor.
 ...
PMID:Parathyroid hormone-related protein (PTHrP) as a regulating factor of endochondral bone formation. 964 17

There is increasing evidence that chondrocyte apoptosis plays an important role in cartilage development, aging and disease. A variety of morphological and biochemical studies have identified apoptotic chondrocytes in both growth plate and articular cartilage of a variety of species. In addition, there is an ever increasing list of diverse stimuli that can induce chondrocyte apoptosis in vitro. A feedback loop regulating chondrocyte apoptosis in the growth plate has been described that includes Indian Hedgehog, parathyroid hormone-related protein and Bcl-2. The molecular mechanism regulating apoptosis in articular cartilage is still under investigation. Future studies should elucidate more fully how abnormal regulation of chondrocyte apoptosis may contribute to the development of chondrodysplasias and chondrosarcomas. Also, it will be of importance to define the relationship between chondrocyte apoptosis and the regulation of chondrocyte-specific gene expression.
 ...
PMID:Chondrocyte apoptosis in development, aging and disease. 969 91

PTHrP is secreted by breast cancer cells in vivo and in vitro. In the breast cancer cell line MCF-7, PTHrP overexpression is associated with increased mitogenesis. We used this cell line to study the mechanism for the proliferative effects of PTHrP. Clonal MCF-7 lines were established overexpressing wild-type PTHrP or PTHrP mutated in the nuclear localization signal (NLS). Mutation of the NLS negated the proliferative effects and nuclear trafficking of PTHrP, indicating that increased mitogenesis is mediated via an intracrine pathway. Cells overexpressing wild-type PTHrP were enriched in G2 + M stage of the cell cycle compared with cells overexpressing NLS-mutated PTHrP, indicating an intracrine role for PTHrP in cell cycle regulation. Wild-type PTHrP also protected MCF-7 cells from serum starvation-induced apoptosis. Cells overexpressing wild-type PTHrP showed significantly greater cell survival than cells overexpressing NLS-mutated PTHrP. The ratios of the apoptosis-regulating proteins Bcl-2 to Bax and Bcl-x(L) to Bax were higher in cells overexpressing wild-type, but not NLS-mutated, PTHrP compared with control cells. These findings suggest that the proliferative effects of PTHrP in breast cancer cells are mediated through regulation of the cell cycle and apoptosis, and that controlling PTHrP production in breast cancer may be therapeutically useful.
 ...
PMID:Intracrine PTHrP protects against serum starvation-induced apoptosis and regulates the cell cycle in MCF-7 breast cancer cells. 1179 15

We investigated the effects of treatment with anti-parathyroid hormone-related protein (1-34) monoclonal murine antibody (anti-PTHrP MoAb) on apoptosis and the differentiation of chondrosarcoma HTB-94 cells. Treatment with anti-PTHrP MoAb accelerated apoptosis of HTB-94 cells in a dose-dependent manner, and anti-PTHrP MoAb also promoted the chondrogenic differentiation of HTB-94 cells. The induction of apoptosis by anti-PTHrP MoAb via imbalance of Bcl-2/Bax ratio and activation of caspase-3 may provide a mechanistic explanation for its potential antitumor effects. Our results suggest the possibility that anti-PTHrP MoAb may be beneficial as a new treatment for chondrosarcoma.
 ...
PMID:Monoclonal antibody to parathyroid hormone-related protein induces differentiation and apoptosis of chondrosarcoma cells. 1296 87

This study examined temporal changes in growth plate apoptosis molecules and growth factors in an animal model of radiation injury with and without a radioprotectant. Thirty weanling 5-week Sprague-Dawley rats underwent right knee irradiation with single-fraction 17.5 Gy while the left served as internal control. Six animals each were sacrificed at 0.5, 1, 2, 3, or 4 weeks after irradiation. Half of the animals received pretreatment with amifostine (WR-2721) radioprotectant. Immunohistochemical staining for PTHrP, Bcl-2, Bax, caspase-3, FGF-2, and TGF-beta was performed. PTHrP decreased to a nadir at 1 week after irradiation but rebounded to above control levels at 2 weeks in the reserve and transitional zones. The radioprotectant amifostine blunted the decrease in PTHrP but kept PTHrP expression lower than controls during the rebound phase in untreated irradiated animals. Hypertrophic zone Bax expression was decreased by amifostine in both irradiated and non-irradiated limbs at 1 and 2 weeks. FGF, TGF-beta, Bcl-2, and caspase levels generally decreased at 1 week and returned thereafter toward control levels. These findings underscore the importance of PTHrP in response to growth plate irradiation and show the novel finding of a decrease in Bax expression with amifostine pretreatment.
 ...
PMID:Temporal changes in PTHrP, Bcl-2, Bax, caspase, TGF-beta, and FGF-2 expression following growth plate irradiation with or without radioprotectant. 1472 67

Human parathyroid hormone-related protein (hPTHrP), identified in patients with paraneoplastic hypercalcemia and expressed by different cell types during development and adult life, plays important roles in many human neoplasms. Immunohistochemical and RT-PCR analyses of hPTHrP and human parathyroid hormone receptor type 1 (PTHR-1) in primary medulloblastoma confirmed their expression in both classic and desmoplastic variants at RNA and protein levels. To evaluate the functional role of hPTHrP, DAOY and D283 medulloblastoma and U87MG glioma cells, expressing high levels of hPTHrP and PTHR-1, were treated with anti-sense oligonucleotides for hPTHrP. Anti-sense treatment produced in all cell lines a decrease of cell proliferation and clonogenic activity and an increase of apoptosis, while addition of exogenous hPTHrP (1-37) prevented these effects. Anti-sense induced the increase of Caspase-3, Fas (CD95) mRNAs and Bax/Bcl-2 mRNA ratio after 12 h of cell treatment. Exogenous hPTHrP (1-37) increased intracellular Ca(2+) concentration in DAOY cells as revealed by FURA. Anti-sense treated cells showed a significant decrease of steady-state levels of intracellular Ca(2+), which was reverted by addition of exogenous hPTHrP (1-37). This study indicates that hPTHrP and PTHR-1 are expressed in medulloblastoma and could promote tumor growth, protecting cells from apoptosis.
 ...
PMID:Human parathyroid hormone-related protein and human parathyroid hormone receptor type 1 are expressed in human medulloblastomas and regulate cell proliferation and apoptosis in medulloblastoma-derived cell lines. 1737 45

Parathyroid hormone-related protein (PTHrP) (107-139), in contrast to the N-terminal fragment PTHrP (1-36), has been shown to interact with the vascular endothelial growth factor (VEGF) system to modulate human osteoblast differentiation. In this study, we evaluated whether this interaction might affect human osteoblastic cell survival. Pre-incubation with PTHrP (107-139) for 1-24 h dose-dependently (0.1-100 nM) inhibited dexamethasone- or etoposide-induced cell death in human osteoblastic MG-63 cells and human osteoblast-like cells from trabecular bone. This effect, but not that elicited by PTHrP (1-36), was abolished by the VEGF receptor (VEGFR)-2 inhibitors SU5614 and SU1498 or VEGFR-2 siRNA transfection in these cells. PTHrP (107-139), but not PTHrP (1-36), at 100 nM, rapidly (within 2 min) increased VEGFR-2 tyrosine-phosphorylation in MG-63 cells; an effect unaffected by several inhibitors of metalloproteinases, neutralizing VEGF(165) or VEGFR-2 antibodies, or the VEGF binding inhibitor CBO-PP1. The latter two antagonists also failed to affect (125)I-[Tyr(116)] PTHrP (107-115) binding to these cells. Consistent with its effect on VEGFR-2 activation, PTHrP (107-139) rapidly induced extracellular signal-regulated kinase (ERK) 1/2 and Akt activaton, and both ERK and phosphatidylinsositol-3 kinase (PI3K) inhibitors abolished its pro-survival effect in human osteoblastic cells. In addition, SU5614 and the latter two types of inhibitors abrogated Runx2 activation by this peptide in MG-63 cells. Transfection with a dominant-negative Runx2 construct abolished the pro-survival effect of PTHrP (107-139), associated with a decrease in Bcl-2/Bax protein ratio. Our findings demonstrate that PTHrP (107-139) interacts with VEGFR-2 to promote human osteoblastic cell survival by a mechanism involving Runx2 activation.
 ...
PMID:Parathyroid hormone-related protein (107-139) increases human osteoblastic cell survival by activation of vascular endothelial growth factor receptor-2. 1865 20

Parathyroid hormone-related protein (PTHrP) is expressed by human prostatic tissues and cancer cell lines. PTHrP enhances tumor cell growth and metastasis in vivo and up-regulates proinvasive integrin alpha6beta4 expression in vitro. Hallmarks of malignant tumor cells include resistance to apoptosis and anchorage-independent cell growth. In this study, we used the human prostate cancer cell lines C4-2 and PC-3 as model systems to study the effects of PTHrP on these processes. We report that PTHrP protects these cells from doxorubicin-induced apoptosis and promotes anchorage-independent cell growth via an intracrine pathway. Conversely, autocrine/paracrine PTHrP action increases apoptosis in C4-2 cells and has no effect on apoptosis in PC-3 cells. The intracrine effects of PTHrP on apoptosis are mediated via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. PTHrP also affects the phosphorylation state of Akt substrates implicated in apoptosis suppression, including glycogen synthase kinase-3 and Bad. The prosurvival effects of PTHrP are accompanied by increases in the ratio of antiapoptotic to proapoptotic members of the Bcl-2 family and in levels of c-myc. PTHrP also increases nuclear factor-kappaB activity via a PI3K-dependent pathway. Integrin alpha6beta4 is known to activate PI3K. Here, we also show that knockdown of integrin alpha6beta4 negates the PTHrP-mediated activation of the PI3K/Akt pathway. Taken together, these observations provide evidence of a link between PTHrP and the PI3K/Akt signaling pathway through integrin alpha6beta4, resulting in the activation of survival pathways. Targeting PTHrP production in prostate cancer may thus prove therapeutically beneficial.
 ...
PMID:Parathyroid hormone-related protein regulates cell survival pathways via integrin alpha6beta4-mediated activation of phosphatidylinositol 3-kinase/Akt signaling. 1958 67

Parathyroid hormone-related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer - it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model caused a delay in primary tumor initiation, inhibited tumor progression, and reduced metastasis to distal sites. Mechanistically, it reduced expression of molecular markers of cell proliferation (Ki67) and angiogenesis (factor VIII), antiapoptotic factor Bcl-2, cell-cycle progression regulator cyclin D1, and survival factor AKT1. PTHrP also influenced expression of the adhesion factor CXCR4, and coexpression of PTHrP and CXCR4 was crucial for metastatic spread. Importantly, PTHrP-specific neutralizing antibodies slowed the progression and metastasis of human breast cancer xenografts. Our data identify what we believe to be new functions for PTHrP in several key steps of breast cancer and suggest that PTHrP may constitute a novel target for therapeutic intervention.
 ...
PMID:PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target. 2254 75


1 2 Next >>