Transcriptional regulation of osteopontin gene in vivo by PEBP2αA/CBFA1 and ETS1 in the skeletal tissues

Sato, Motohiko; Morii, Eiichi; Komori, Toshihisa; Kawahata, Hirohisa; Sugimoto, Masamichi; Terai, Kunihiro; Shimizu, Hideo; Yasui, Takahiro; Ogihara, Hideki; Yasui, Natsuo; Ochi, Takahiro; Kitamura, Yukihiko; Ito, Yoshiaki; Nomura, Shosaku

doi:10.1038/sj.onc.1202064

Cited by 254 publications

(217 citation statements)

References 32 publications

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“…17,18 Recently, three functional polymorphisms (À66T/G, À156del/G and À443T/C) on the promoter region of OPN gene have been found to affect gene expression by altering transcriptional activity 19 and reported to be associated with several diseases, including pseudoxanthoma elasticum, stroke and chronic hepatitis C. [20][21][22] The insertion of guanine base at position À156 (À156G allele) on the OPN promoter generates a Runx2 binding site so that the binding of Runx2 factor to the À156G position promotes OPN transcription. 19 In the present study, we investigated the association between diastolic dysfunction and the À156del/G polymorphism on the OPN promoter in patients with hypertension.…”

Section: Introductionmentioning

confidence: 99%

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population

et al. 2011

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Heart failure with preserved ejection fraction is recently highlighted as a major health problem, and diastolic dysfunction associated with hypertension has a dominant role in the development of heart failure with preserved ejection fraction. Osteopontin (OPN) is a secreted phosphoprotein, which mediates fibrosis. In animal models, OPN is upregulated in response to pressure overload and is thought to be involved in systolic dysfunction. However, the functional role of OPN in diastolic dysfunction is unknown. The guanine base insertion polymorphism at À156 position of the OPN promoter is postulated to upregulate the transcription of OPN in human. To investigate whether À156del/G polymorphism of OPN promoter is associated with diastolic dysfunction in hypertensive hearts, the patients with hypertension have been genotyped for variants of À156del/G polymorphism by genomic sequencing. Diastolic function of the left ventricle was estimated as the ratio of early to atrial filling (E/A ratio), obtained by pulsed-Doppler derived transmitral flow in echocardiographic analysis. The patients with À156G allele displayed lower E/A ratio compared with those with À156del/del genotype, suggesting exacerbated diastolic function. Notably, in case of the population with diabetes mellitus, the patients with À156G allele showed significant association with lower E/A ratio, compared with À156del/À156del patients. Multiple linear regression analysis revealed that prevalence of À156G allele was an independent factor for lowering E/A ratio. The À156del/G genetic variants of OPN promoter were associated with decreased E/A ratio in hypertensive patients. These results suggest that OPN has a functional role in the development of diastolic dysfunction in hypertensive hearts.

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Section: Introductionmentioning

confidence: 99%

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population

et al. 2011

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“…Unlike many proto-oncogenes activated by a gain of function mutation, osteopontin is not typically mutated during stepwise tumorigenesis (24). Instead, various responsive elements in its promoter regulate osteopontin expression for its diverse physiologic roles (129)(130)(131)(132), and it is presumably these elements that allow the overexpression of osteopontin in certain cancers.…”

Section: Growth Factor Receptor Pathways and Osteopontinmentioning

confidence: 99%

The Role of Osteopontin in Tumor Progression and Metastasis in Breast Cancer

Rodrigues

Teixeira

Schmitt

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The use of cancer biomarkers to anticipate the outlines of disease has been an emerging issue, especially as cancer treatment has made such positive steps in the last few years. Progress in the development of consistent malignancy markers is imminent because advances in genomics and bioinformatics have allowed the examination of immense amounts of data. Osteopontin is a phosphorylated glycoprotein secreted by activated macrophages, leukocytes, and activated T lymphocytes, and is present in extracellular fluids, at sites of inflammation, and in the extracellular matrix of mineralized tissues. Several physiologic roles have been attributed to osteopontin, i.e., in inflammation and immune function, in mineralized tissues, in vascular tissue, and in kidney. Osteopontin interacts with a variety of cell surface receptors, including several integrins and CD44. Binding of osteopontin to these cell surface receptors stimulates cell adhesion, migration, and specific signaling functions. Overexpression of osteopontin has been found in a variety of cancers, including breast cancer, lung cancer, colorectal cancer, stomach cancer, ovarian cancer, and melanoma. Moreover, osteopontin is present in elevated levels in the blood and plasma of some patients with metastatic cancers. Therefore, suppression of the action of osteopontin may confer significant therapeutic activity, and several strategies for bringing about this suppression have been identified. This review looks at the recent advances in understanding the possible mechanisms by which osteopontin may contribute functionally to malignancy, particularly in breast cancer. Furthermore, the measurement of osteopontin in the blood or tumors of patients with cancer, as a way of providing valuable prognostic information, will be discussed based on emerging clinical data. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1087 -97)

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“…Several known cis-acting transcription factors have been described and most of them have been localized to a conserved region at 250 bp upstream of the proximal promoter. Potential binding sites for transcriptional regulators, such as AP-1, Myc, Oct-1, USF, v-Src, TGF-b/BMPs/Smad/Hox, Wnt/ b-catenin/APC/GSK-3b/Tcf-4, Ras/RRF, TF53, Runx2, and ETS family members, have been identified (14)(15)(16)(17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Abnormal Expression of the ERG Transcription Factor in Prostate Cancer Cells Activates Osteopontin

Flajollet

Tian

Flourens

et al. 2011

Molecular Cancer Research

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Osteopontin (OPN) is an extracellular matrix glycophosphoprotein that plays a key role in the metastasis of a wide variety of cancers. The high level of OPN expression in prostate cells is associated with malignancy and reduced survival of the patient. Recent studies on prostate cancer (PCa) tissue have revealed recurrent genomic rearrangements involving the fusion of the 5 0 untranslated region of a prostate-specific androgen-responsive gene with a gene coding for transcription factors from the ETS family. The most frequently identified fusion gene is TMPRSS2:ERG, which causes ERG protein overexpression in PCa cells. ERG is a transcription factor linked to skeletogenesis. This study was designed to test whether ERG and the product of the TMPRSS2:ERG fusion gene modulate OPN gene expression in PCa cells. To characterize ERG and TMPRSS2:ERG transcriptional activity of OPN, we focused on ETS binding sites (EBS) localized in conserved regions of the promoter. Using in vitro and in vivo molecular assays, we showed that ERG increases OPN expression and binds to an EBS (nt À115 to À118) in the OPN promoter. Moreover, stable transfection of prostate tumor cell lines by TMPRSS2:ERG upregulates endogenous OPN expression. Finally, in human prostate tumor samples, detection of the TMPRSS2:ERG fusion gene was significantly associated with OPN overexpression. Taken together, these data suggest that OPN is an ERG-target gene in PCa where the abnormal expression of the transcription factor ERG, due to the TMPRSS2: ERG fusion, disturbs the expression of genes that play an important role in PCa cells and associated metastases. Mol Cancer Res; 9(7); 914-24. Ó2011 AACR.

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Transcriptional regulation of osteopontin gene in vivo by PEBP2αA/CBFA1 and ETS1 in the skeletal tissues

Cited by 254 publications

References 32 publications

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population

The Role of Osteopontin in Tumor Progression and Metastasis in Breast Cancer

Abnormal Expression of the ERG Transcription Factor in Prostate Cancer Cells Activates Osteopontin

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