Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P67775 (alpha isoform)
 797 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chromosome region 11q is frequently deleted in colorectal cancers. The PPP2R1B tumor suppressor gene, encoding the beta isoform of the A subunit of serine/threonine-specific protein phosphatase 2A (PP2A-Abeta), located at 11q22-23, is inactivated in patients with cancer. The present study investigated whether or not PP2A-Abeta is altered in colorectal cancers. We searched for alterations of the PPP2R1B gene and interactions between PP2A-Abeta and PP2A-C proteins in 50 surgically resected colorectal cancer tissues. Missense mutations and homozygous deletions of the PPP2R1B gene were found in 4 of 50 patients (8%) and in 1 of 50 patients, respectively, with colorectal cancers. Deletions and/or point mutations within 412-601 amino acid sequences (binding regions of PP2A-C protein) of the PPP2R1B gene derived from colorectal cancer tissues inhibited co-immunoprecipitation of PP2A-Abeta and PP2A-C proteins. These finding suggested that the PPP2R1B gene functions as a tumor suppressor gene and acts as a molecular switch that becomes active in response to specific up-stream signals. Upon activation, the gene alters the activities of specific downstream target proteins for the cell cycle regulations and/or metabolism in some colorectal cancers.
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PMID:PPP2R1B gene alterations inhibit interaction of PP2A-Abeta and PP2A-C proteins in colorectal cancers. 1476 17

Tumour cell invasiveness is crucial for cancer metastasis and is not yet understood. Here we describe two functional screens for proteins required for the invasion of fibrosarcoma cells that identified the molecular chaperone heat shock protein 90 (hsp90). The hsp90 alpha isoform, but not hsp90 beta, is expressed extracellularly where it interacts with the matrix metalloproteinase 2 (MMP2). Inhibition of extracellular hsp90 alpha decreases both MMP2 activity and invasiveness. This role for extracellular hsp90 alpha in MMP2 activation indicates that cell-impermeant anti-hsp90 drugs might decrease invasiveness without the concerns inherent in inhibiting intracellular hsp90.
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PMID:Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. 1517 Apr 57

Folates are essential for cell survival and are required for numerous biochemical processes. The human alpha isoform folate receptor (alphahFR) has a very high affinity for folic acid and is considered an essential component in the cellular accumulation of folates and folate analogues used in chemotherapy. The expression of alphahFR is not detected inmost normal tissues. In contrast, high levels of the expression of alphahFR have been reported in a variety of cancer cells. The significance of alphahFR overexpression in malignant tissues has not been elucidated, but it is possible that it promotes cell proliferation not only by mediating folate uptake but also by generating other regulatory signals. The purpose of the present study was to evaluate alphahFR as a potential target for the treatment of breast cancer. Initial studies were done in nasopharyngeal carcinoma (KB) cells, which express high levels of alphahFR. In KB cells, antisense oligodeoxyribonucleotides (ODN) complementary to the alphahFR gene sequences were found to reduce newly synthesized alphahFR protein up to 60%. To examine the effect of alphahFR antisense ODNs in a panel of cultured human breast cancer cell lines, we used a tumor cell-targeted, transferrin-liposome-mediated delivery system. The data show that alphahFR antisense ODNs induced a dose-dependent decrease in cell survival. Finally, we determined that alphahFR antisense ODNs sensitized MDA-MB-435 breast cancer cells by 5-fold to treatment with doxorubicin. The data support the application of alphahFR antisense ODNs as a potential anticancer agent in combination with doxorubicin.
Mol Cancer Ther 2004 Dec
PMID:Antisense oligonucleotides targeted to the human alpha folate receptor inhibit breast cancer cell growth and sensitize the cells to doxorubicin treatment. 1563 43

The monoclonal antibody (mAb) MOv18 binds the membrane alpha isoform of the folate receptor (FR) which is overexpressed in human ovarian carcinoma cells. Exploiting the targeting capacity of this mAb, we developed and preclinically validated a protocol for the stable labeling of the mAb with 90Y, an isotope which has shown promise in cancer radioimmunotherapy. MOv18 was derivatized with the stable macrocyclic ligand p-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (Bz-DOTA). MOv18-Bz-DOTA conjugates were labeled with 90Y or 111In under metal-free and good laboratory practice conditions. At the optimal Bz-DOTA/mAb derivatization ratio of 4-5, conjugates maintained binding activity up to 6 months, were efficiently labeled with 90Y or 111In (mean labeling yield 85 and 64%, associated to a final mean specific activity of 74 and 37 MBq/mg) and displayed a mean immunoreactivity of 60 and 58%, respectively. The radiolabeled preparations were stable in human serum, with >97% radioactivity associated to mAb at 48 h after labeling. The ability of 90Y- and 111In-MOv18 to localize FR on tumors in vivo was analyzed in nude mice bearing tumors induced by isogenic cell lines differing only in the presence or absence of the relevant antigen [A431FR (FR-positive) and A431tMock (FR-negative)]. In vivo biodistribution in organs other than tumor was comparable in non-tumor-, A431tMock- and A431FR-bearing mice, whereas the median tumor uptake of the radiolabeled reagents, expressed as area under the curve (AUC) and maximum uptake (Umax), was significantly higher (sixfold to sevenfold) in A431FR than in A431tMock tumors (P=0.0465 and P=0.0332, respectively). Mean maximum uptake (% ID/g) for 90Y-MOv18 was 53.7 and 7.4 in A431FR and A431tMock respectively; corresponding values for 111In-Mov18 were 45.0 and 11.3. These data demonstrate the feasibility of 90Y-labeling of MOv18 without compromising antibody binding ability and the immunoreagent-specific localization in vivo on FR-expressing tumors, suggesting the suitability of 90Y-MOv18 for clinical studies.
Cancer Immunol Immunother 2005 Dec
PMID:90Y Labeling of monoclonal antibody MOv18 and preclinical validation for radioimmunotherapy of human ovarian carcinomas. 1592 78

Estrogen receptors (alpha and beta) are members of the steroid/thyroid nuclear receptors superfamily of ligand-dependent transcription factors. Impact of the alpha isoform of estrogen receptor (ER) on breast cancer etiology and progression is now well established. Current therapeutic strategy to treat ER-positive breast cancer relies on the blockade of ER trancriptional activity by antiestrogens. Data accumulated during the last five years on the mechanism of action of ER enable one to foresee new strategies. These data indeed reveal that ER is not statically bound to DNA at promoter sites of genes regulating cell proliferation and/or differentiation, but rather behaves as a very mobile protein continuously shuttling between targets located within various cellular compartments (i.e. membrane, microsomes, nucleus...). This allows the receptor to generate both non-genomic and genomic responses. Ligands, growth factors and second messengers produced downstream of activated membrane receptors modulate ER-mediated responses by interfering with the traffic patterns of the receptor, as well as by locally blocking its transient anchorage. Changes in ER turnover rate associated with these regulatory processes seem also to strongly influence the ability of the receptor to mediate gene transactivation. The present paper surveys these biological data and analyzes how they may be integrated into new drug design programs aimed at expanding our therapeutic armamentarium against breast cancer.
Curr Cancer Drug Targets 2006 Feb
PMID:Estrogen receptor alpha: impact of ligands on intracellular shuttling and turnover rate in breast cancer cells. 1647 75

The aim of this study was to investigate the role of TAp63 and DeltaNp63 isoforms in uterine cervical cancers. The messenger RNA (mRNA) and protein expressions of TA and DeltaN forms as well as alpha, beta, and gamma isoforms of p63 were studied in seven SiHa, ME-180, SNU17, SNU902, SNU1160, SNU703, and SNU1299 human papillomavirus (HPV)-positive uterine cervical squamous cell carcinoma (SCC) cell lines, one HT3 HPV-negative SCC cell line, and one HeLa adenocarcinoma cell line using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. Fresh nonneoplastic and neoplastic tissues of uterine cervical and endometrial cancers were also studied. RT-PCR for TA and DeltaN form and three isoforms of p63 showed positive bands for both TA and DeltaN forms and for all three isoforms in cervical cancer cell lines but weak band for alpha isoform in HPV-negative HT3 SCC cell line and no band for beta isoform in HeLa adenocarcinoma cell line. RT-PCR for TA and DeltaN and three isoforms of p63 mRNA in tissue samples showed positive bands in almost all samples, except for gamma isoform, the expression was weak or absent in nonneoplastic tissues compared with neoplastic tissues. In western blotting, cancer cell lines and both nonneoplastic and neoplastic tissue samples showed expression of TA and DeltaN, and gamma isoform but beta isoform expression with or without alpha isoform was only found in cancer cell lines and neoplastic tissues. beta isoform, possibly of DeltaNp63, may be considered as an important isoform in uterine cervical squamous cell carcinogenesis.
Int J Gynecol Cancer
PMID:Reverse transcription-polymerase chain reaction and western blotting analysis for detection of p63 isoforms in uterine cervical cancers. 1688 78

Radiotherapy is the primary and most important adjuvant therapy for malignant gliomas. Although the mechanism of radiation resistance in gliomas has been studied for decades, it is still not clear how the resistance is related with functions of molecular chaperones in the endoplasmic reticulum. Calreticulin (CRT) is a Ca(2+)-binding molecular chaperone in the endoplasmic reticulum. Recently, it was reported that changes in intracellular Ca(2+) homeostasis play a role in the modulation of apoptosis. In the present study, we found that the level of CRT was higher in neuroglioma H4 cells than in glioblastoma cells (U251MG and T98G), and was well correlated with the sensitivity to gamma-irradiation. To examine the role of CRT in the radiosensitivity of malignant gliomas, the CRT gene was introduced into U251MG cells, which express low levels of CRT, and the effect of overexpression of CRT on the radiosensitivity was examined. The cells transfected with the CRT gene exhibited enhanced radiation-induced apoptosis compared with untransfected control cells. In CRT-overexpressing cells, cell survival signaling via Akt was markedly suppressed. Furthermore, the gene expression of protein phosphatase 2Ac alpha (PP2Ac alpha), which is responsible for the dephosphorylation and inactivation of Akt, was up-regulated in CRT-overexpressing cells, and the regulation was dependent on Ca(2+). Thus, overexpression of CRT modulates radiation-induced apoptosis by suppressing Akt signaling through the up-regulation of PP2Ac alpha expression via altered Ca(2+) homeostasis. These results show the novel mechanism by which CRT is involved in the regulation of radiosensitivity and radiation-induced apoptosis in malignant glioma cells.
Cancer Res 2006 Sep 01
PMID:Calreticulin, a molecular chaperone in the endoplasmic reticulum, modulates radiosensitivity of human glioblastoma U251MG cells. 1695 Nov 81

Type 2 topoisomerases, in particular the alpha isoform in human cells, play a key role in cohesion and sister chromatid separation during mitosis. These enzymes are thus vital for cycling cells and are obvious targets in cancer chemotherapy. Evidence obtained in yeast and Xenopus model systems indicates that conjugation of topoisomerase 2 with small ubiquitin-like modifier (SUMO) proteins is required for its mitotic functions. Here, we provide biochemical and cytologic evidence that topoisomerase 2 alpha is conjugated to SUMO-2/3 during interphase and mitosis in response to topoisomerase 2 inhibitors and "poisons" (ICRF-187, etoposide, doxorubicin) that stabilize catalytic intermediates (cleavage complexes, closed clamp forms) of the enzyme onto target DNA. During mitosis, SUMO-2/3-modified forms of topoisomerase 2 alpha localize to centromeres and chromosome cores/axes. However, centromeres are unresponsive to inhibitors during interphase. Furthermore, formation of topoisomerase 2 alpha-SUMO-2/3 conjugates within mitotic chromosomes strongly correlates with incomplete chromatid decatenation and decreases progressively as cells approach the metaphase-anaphase transition. We also found that the PIASy protein, an E3 ligase for SUMO proteins, colocalizes with SUMO-2/3 at the mitotic chromosomal cores/axes and is necessary for both formation of SUMO-2/3 conjugates and proper chromatid segregation. We suggest that the efficacy of topoisomerase inhibitors to arrest cells traversing mitosis may relate to their targeting of topoisomerase 2 alpha-SUMO-2/3 conjugates that concentrate at mitotic chromosome axes and are directly involved in chromatid arm separation.
Cancer Res 2008 Apr 01
PMID:Conjugation of human topoisomerase 2 alpha with small ubiquitin-like modifiers 2/3 in response to topoisomerase inhibitors: cell cycle stage and chromosome domain specificity. 1838 49

Topoisomerase II (Top2) is a ubiquitous nuclear enzyme that relieves torsional stress in chromosomal DNA during various cellular processes. Agents that target Top2, involving etoposide, doxorubicin, and mitoxantrone, are among the most effective anticancer drugs used in the clinic. Mammalian cells possess two genetically distinct Top2 isoforms, both of which are the target of these agents. Top2alpha is essential for cell proliferation and is highly expressed in vigorously growing cells, whereas Top2beta is nonessential for growth and has recently been implicated in treatment-associated secondary malignancies, highlighting the validity of a Top2alpha-specific drug for future cancer treatment; however, no such agent has been hitherto reported. Here we show that NK314, a novel synthetic benzo[c]phenanthridine alkaloid, targets Top2alpha and not Top2beta in vivo. Unlike other Top2 inhibitors, NK314 induces Top2-DNA complexes and double-strand breaks (DSBs) in an alpha isoform-specific manner. Heterozygous disruption of the human TOP2alpha gene confers increased NK314 resistance, whereas TOP2beta homozygous knock-out cells display increased NK314 sensitivity, indicating that the alpha isoform is the cellular target. We further show that the absence of Top2beta does not alleviate NK314 hypersensitivity of cells deficient in non-homologous end-joining, a critical pathway for repairing Top2-mediated DSBs. Our results indicate that NK314 acts as a Top2alpha-specific poison in mammalian cells, with excellent potential as an efficacious and safe chemotherapeutic agent. We also suggest that a series of human knock-out cell lines are useful in assessing DNA damage and repair induced by potential topoisomerase-targeting agents.
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PMID:NK314, a topoisomerase II inhibitor that specifically targets the alpha isoform. 1859 31

We have previously shown that tetraploid cancer cells succumb through a p53-dependent apoptotic pathway when checkpoint kinase 1 (Chk1) is depleted by small interfering RNAs (siRNAs) or inhibited with 7-hydroxystaurosporine (UCN-01). Here, we demonstrate that Chk1 inhibition results in the activating phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Depletion of p38 MAPK by transfection with a siRNA targeting the alpha isoform of p38 MAPK (p38alpha MAPK) abolishes the phosphorylation of p53 on serines 15 and 46 that is induced by Chk1 knockdown. The siRNA-mediated downregulation and pharmacological inhibition of p38alpha MAPK (with SB 203580) also reduces cell death induced by Chk1 knockdown or UCN-01. These results underscore the role of p38 MAPK as a pro-apoptotic kinase in the p53-dependant pathway for the therapeutic elimination of polyploidy cells.
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PMID:Chk1 inhibition activates p53 through p38 MAPK in tetraploid cancer cells. 1864 43


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