Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hedgehog, FGF, VEGF, and Notch signaling pathways network together for vascular remodeling during embryogenesis and carcinogenesis. HHIP1 (HHIP) is an endogenous antagonist for SHH, IHH, and DHH. Here, comparative integromics analyses on HHIP family members were performed by using bioinformatics and human intelligence. HHIP1, HHIP2 (HHIPL1 or KIAA1822) and HHIP3 (HHIPL2 or KIAA1822L) constitute human HHIP gene family. Rat Hhip1, Hhip2, and Hhip3 genes were identified within AC107504.4, AC094820.6, and AC134264.2 genome sequences, respectively. HHIP-homologous (HIPH) domain with conserved 18 Cys residues was identified as the novel domain conserved among mammalian HHIP1, HHIP2, and HHIP3 orthologs. HHIP1 mRNA was expressed in coronary artery endothelial cells, prostate, and rhabdomyosarcoma. HHIP2 mRNA was expressed in trabecular bone cells. HHIP3 mRNA was expressed in testis, thyroid gland, osteoarthritic cartilarge, pancreatic cancer, and lung cancer. Promoters of HHIP family genes were not well conserved between human and rodents. Although GLI-, CSL-, and HES/HEY-binding sites were not identified, eleven bHLH-binding sites were identified within human HHIP1 promoter. Expression of HES/HEY family members, including HES1, HES2, HES3, HES4, HES5, HES6, HES7, HEY1, HEY2 and HEYL, in coronary artery endothelial cells was not detected in silico. Up-regulation of HHIP1 due to down-regulation of Notch-CSL-HES/HEY signaling cascade repressing bHLH transcription factors results in down-regulation of the Hedgehog-VEGF-Notch signaling cascade. On the other hand, down-regulation of HHIP1 due to up-regulation of Notch signaling in vascular endothelial cells during angiogenesis results in up-regulation of the Hedgehog-VEGF-Notch signaling cascade. Because HHIP1 is the key molecule for vascular remodeling, HHIP1 is the pharmacogenomics target in the fields of oncology and vascular medicine.
Int J Mol Med 2006 Feb
PMID:Comparative genomics on HHIP family orthologs. 1639 42

The human forkhead box O1A (FOXO1A) gene on chromosome 13q14.1 is a key transcription factor in insulin signaling in liver and adipose tissue and plays a central role in the regulation of key pancreatic beta-cell genes including IPF1. We hypothesized that sequence variants of FOXO1A contribute to the observed defects in hepatic and peripheral insulin action and altered beta-cell compensation that characterize type 2 diabetes (T2DM). To test this hypothesis, we screened the three exons, 3' untranslated region, and 5' flanking region for sequence variants in Caucasian and African-American individuals with early onset (<45 years) T2DM. We identified only six variants; none altered the coding sequence, and except for one variant in the 3' untranslated region, they were rare or absent in Caucasians. To increase coverage of the gene, we selected seven additional variants in the large first intron and 5' flanking region, thus providing 13 variants that spanned 116.4kb. Based on frequency and linkage disequilibrium patterns in a subset of individuals, we selected eight SNPs to type in a Caucasian population comprising 192 unrelated nondiabetic control individuals and 192 individuals with T2DM, and 10 SNPs to type in 182 controls and 352 diabetic individuals of African-American ancestry. No variant was associated with T2DM (African-Americans, p>0.08; Caucasians, p>0.09). Of the 8 Caucasian SNPs, six comprised a single haplotype block spanning over 100kb and including most of the large first intron. In contrast, no block was observed among SNPs typed in African-Americans. No haplotype was associated with T2DM. FOXO1A variation is rare and is unlikely to contribute to T2DM in either Caucasian or African-American populations.
Mol Genet Metab 2006 Jun
PMID:Analysis of FOXO1A as a candidate gene for type 2 diabetes. 1649 30

Alveolar rhabdomyosarcoma (ARMS) is a soft tissue cancer in which chromosomal translocations generate PAX3-FKHR and PAX7-FKHR gene fusions. To improve the approach for fusion detection in archival samples, we developed a real-time reverse transcriptase-polymerase chain reaction assay for these fusion transcripts. By incorporating consensus primers and gene-specific probes, both presence and subtype of the fusion were determined in one assay. We applied this approach to a convenience sample of 78 formalin-fixed, paraffin-embedded ARMS tumors from the Intergroup Rhabdomyosarcoma Study (IRS)-III clinical trial and obtained satisfactory results in 59 (76%) cases. The distribution of fusion types was 35 (59%) PAX3-FKHR, 11 (19%) PAX7-FKHR, and 13 fusion-negative (22%). In a subsequent clinical analysis, we found that IRS-III ARMS cases analyzed for fusion status had a significantly improved outcome compared to IRS-III ARMS cases that were not available for fusion analysis. The basis of this outcome could not be explained by known prognostic clinical factors, and multivariate analysis confirmed that our convenience sample was not representative of the whole IRS-III cohort. In conclusion, although these robust assays provide new opportunities for correlative studies of archival material, our first application illustrates an important limitation of using a convenience sample for molecular-clinical correlative studies.
J Mol Diagn 2006 May
PMID:Examination of gene fusion status in archival samples of alveolar rhabdomyosarcoma entered on the Intergroup Rhabdomyosarcoma Study-III trial: a report from the Children's Oncology Group. 1664 6

The integrity of the feto-maternal interface is critical for survival of the conceptus. This interface, consisting of the maternal decidua and the invading placental trophoblast, is exposed to profound changes in oxygen tension during pregnancy. We demonstrate that human endometrial stromal cells become extraordinarily resistant to oxidative stress-induced apoptosis upon decidualization in response to cAMP and progesterone signaling. This differentiation process is associated with the induction of the forkhead transcription factor FOXO1, which in turn increases the expression of the mitochondrial antioxidant manganese superoxide dismutase. However, silencing of FOXO1 did not increase the susceptibility of decidualized cells to oxidative cell death. Comparative analysis demonstrated that hydrogen peroxide, a source of free radicals, strongly induces FOXO3a mRNA and protein expression in undifferentiated human endometrial stromal cells but not in decidualized cells. Expression of a constitutively active FOXO3a mutant elicited apoptosis in decidualized cells. Furthermore, silencing of endogenous FOXO3a in undifferentiated cells abrogated apoptosis induced by hydrogen peroxide. These results suggest that the induction of FOXO1 may enhance the ability of decidualized cells to prevent oxidative damage while the simultaneous repression of FOXO3a expression disables the signaling pathway responsible for oxidative cell death. The differential regulation of FOXO expression provides the decidua with a robust system capable of coping with prolonged episodes of oxidative stress during pregnancy.
Mol Endocrinol 2006 Oct
PMID:Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization. 1670

The human endometrium undergoes cyclical waves of proliferation, differentiation and apoptosis in response to the rise and fall in ovarian oestradiol and progesterone levels. These hormonal responses in endometrial cells must be tightly kept in check to safeguard tissue homeostasis throughout reproductive life. The discovery that differentiating endometrium highly expresses the tumour suppressor p53, the forkhead transcription factor FOXO1, and promyelocytic leukaemia zinc finger protein (PLZF) has provided new insights into the molecular basis of life and death decisions in response to sex steroid hormones.
J Mol Endocrinol 2006 Jun
PMID:Death or survival--progesterone-dependent cell fate decisions in the human endometrial stroma. 1672 Jul 11

Myoblast cell cycle exit and differentiation are mediated in part by down-regulation of cyclin D1 and associated cyclin-dependent kinase (Cdk) activity. Because rhabdomyosarcoma may represent a malignant tumor composed of myoblast-like cells failing to exit the cell cycle and differentiate, we considered whether excess Cdk activity might contribute to this biology. Cyclin D-dependent Cdk4 and Cdk6 were expressed in most of a panel of six human rhabdomyosarcoma-derived cell lines. Cdk4 was expressed in 73% of alveolar and embryonal rhabdomyosarcoma tumors evaluated using a human tissue microarray. When challenged to differentiate by mitogen deprivation in vitro, mouse C2C12 myoblasts arrested in G(1) phase of the cell cycle, whereas four in the panel of rhabdomyosarcoma cell lines failed to do so. C2C12 myoblasts maintained in mitogen-rich media and exposed to a Cdk4/Cdk6 inhibitor PD 0332991 accumulated in G(1) cell cycle phase. Similar treatment of rhabdomyosarcoma cell lines caused G(1) arrest and prevented cell accumulation in vitro, and it delayed growth of rhabdomyosarcoma xenografts in vivo. Consistent with a role for Cdk4/Cdk6 activity as a regulator of myogenic differentiation, we observed that PD 0332991 exposure promoted morphologic changes and enhanced the expression of muscle-specific proteins in cultured myoblasts and in the Rh30 cell line. Our findings support the concept that pharmacologic inhibition of Cdk4/Cdk6 may represent a useful therapeutic strategy to control cell proliferation and possibly promote myogenic differentiation in rhabdomyosarcoma.
Mol Cancer Ther 2006 May
PMID:Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells. 1673 63

The nutrient response mediated by feeding or fasting plays an important role in controlling gluconeogenic gene expression such as glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxylase (PEPCK). The FOXO family of forkhead transcription factor Foxo1 (mouse FOXO1) is a key regulator that stimulates the expression of gluconeogenic genes in the nucleus but is phosphorylated by Akt (also known as protein kinase B; PKB) and translocated to the cytoplasm in response to insulin. Although it has been widely accepted that the cellular signaling of insulin represses Foxo1 function through Akt-dependent phosphorylation, the molecular mechanism behind the modulation of Foxo1 function by nutrient responses, including feeding or fasting, remains unknown in vivo. We investigated the consequences of the nutritional changes in Akt-mediated Foxo1 phosphorylation and translocation in the liver using control C57BL/6 and diabetic db/db mice. We found that feeding promotes the phosphorylation and nuclear exclusion of Foxo1, whereas fasting counteracted them in C57BL/6 mice. Notably, db/db mice exhibited constitutive phosphorylation but dominant nuclear accumulation of Foxo1, even though CREB phosphorylation usually occurred in the fasted status. Furthermore, in contrast to C57BL/6 mice, the expression of G6Pase, PEPCK and PGC-1alpha genes during feeding was not down-regulated in db/db mice. Thus, we suggest that the accurate regulation of Foxo1 via Akt-dependent phosphorylation is required for physiological adaptation to different nutritional statuses.
Int J Mol Med 2006 Sep
PMID:Nutrient control of phosphorylation and translocation of Foxo1 in C57BL/6 and db/db mice. 1686 27

Cytogenetic and molecular studies have shown that approximately 80% of cases of alveolar rhabdomyosarcoma (ARMS) have consistent chromosomal translocation of either t(2;13) or t(1;13), resulting in either PAX3-FKHR or PAX7-FKHR gene fusions. However, 20% of the cases diagnosed histologically are negative for these fusion genes. The clinical and pathological properties of the so-called fusion gene negative tumors remain to be defined. We present an unusual case of a 7-year-old boy who developed three separate primary ARMS over a 5-year period, with the first tumor diagnosed at the age of 12 months. The tumors were negative for the characteristic translocations, t(2;13) or t(1;13), but showed evidence of low-level chromosomal instability and a reciprocal chromosomal translocation t(6;11)(q27;q13). PCR amplification of the p53 gene, exons 2-11, followed by DNA sequencing did not detect any germline p53 mutation. These clinical and cytogenetic features have not been reported previously in ARMS. The findings suggest that cytogenetic abnormalities of chromosome 6 may be associated with the development of early onset multiple ARMS in a subgroup of pediatric patients as seen in this case.
Exp Mol Pathol 2007 Feb
PMID:Cytogenetic and molecular studies of an unusual case of multiple primary alveolar rhabdomyosarcomas: low-level chromosomal instability and reciprocal translocation t(6;11). 1709 83

A number of solid tumors, such as alveolar rhabdomyosarcoma, synovial sarcoma, and myxoid liposarcoma, are associated with recurrent translocation events that encode fusion proteins. Ewing's sarcoma is a pediatric tumor that serves as a prototype for this tumor class. Ewing's sarcomas usually harbor the (11;22)(q24;q12) translocation. The t(11;22) encodes the EWS/FLI fusion oncoprotein. EWS/FLI functions as an aberrant transcription factor, but the key target genes that are involved in oncogenesis are largely unknown. Although some target genes have been defined, many of these have been identified in heterologous model systems with uncertain relevance to the human disease. To understand the function of EWS/FLI and its targets in a more clinically relevant system, we used retroviral-mediated RNAi to "knock-down" the fusion protein in patient-derived Ewing's sarcoma cell lines. By combining transcriptional profiling data from three of these lines, we identified a conserved transcriptional response to EWS/FLI. The gene that was most reproducibly up-regulated by EWS/FLI was NR0B1. NR0B1 is a developmentally important orphan nuclear receptor with no previously defined role in oncogenesis. We validated NR0B1 as an EWS/FLI-dysregulated gene and confirmed its expression in primary human tumor samples. Functional studies revealed that ongoing NR0B1 expression is required for the transformed phenotype of Ewing's sarcoma. These studies define a new role for NR0B1 in oncogenic transformation and emphasize the utility of analyzing the function of EWS/FLI in Ewing's sarcoma cells.
Mol Cancer Res 2006 Nov
PMID:NR0B1 is required for the oncogenic phenotype mediated by EWS/FLI in Ewing's sarcoma. 1711 43

Common practice to evaluate the efficacy of any compound as drug is done in cell-based in vitro system followed by in vivo murine model prior to clinical trial in human. Cardiac glycosides are very effective to kill human cells, but not murine cells. In this report, we describe the comparative molecular mechanism of oleandrin, a cardiac glycoside action in human and murine cells. Treatment with oleandrin facilitated nuclear translocation of FKHR in human, but not murine cells by dephosphorylating Akt. It activated MAPK and JNK in human, but not in murine cells and also induced expression of FasL leads to apoptosis in human cells as detected by assaying caspases activation, PARP cleavage, nuclear fragmentation, and annexin staining. Oleandrin interacted with human plasma membrane as evaluated by HPLC, altered its fluidity as detected by DPH binding, inhibited Na+/K+-ATPase activity, and increased intracellular free Ca2+ level followed by calcineurin activity only in human, but not in murine cells. Results suggest that human plasma membrane might be different than murine, which interact with oleandrin that disturb Na+/K+-ATPase pump resulting in the calcification followed by induction of Ca2+-dependent cellular responses such as apoptosis.
Mol Immunol 2007 Mar
PMID:Oleandrin induces apoptosis in human, but not in murine cells: dephosphorylation of Akt, expression of FasL, and alteration of membrane fluidity. 1717 71


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