Two novel VHL targets, TGFBI (BIGH3) and its transactivator KLF10, are up-regulated in renal clear cell carcinoma and other tumors

Ivanov, Sergey V.; Ivanova, Alla V.; Salnikow, Konstantin; Timofeeva, Olga; Subramaniam, Malayannan; Lerman, Michael I.

doi:10.1016/j.bbrc.2008.03.066

Cited by 52 publications

(49 citation statements)

References 39 publications

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“…It was also reported that the C-terminal fragment of ␤ig-h3 was required for apoptosis in human cancer cells (26). In addition, overexpression of ␤ig-h3 was found in various tumors in different organs including the kidney and brain (11). Increased urinary concentrations of ␤ig-h3 have also been reported in type-2 diabetes mellitus (4) and in chronic cyclosporine nephrotoxicity (14).…”

Section: Discussionmentioning

confidence: 93%

Increased urinary excretion of nephrin, podocalyxin, and βig-h3 in women with preeclampsia

Wang

Zhao²,

Loyd³

et al. 2012

American Journal of Physiology-Renal Physiology

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Wang Y, Zhao S, Loyd S, Groome LJ. Increased urinary excretion of nephrin, podocalyxin, and ␤ig-h3 in women with preeclampsia. Am J Physiol Renal Physiol 302: F1084 -F1089, 2012. First published February 1, 2012 doi:10.1152/ajprenal.00597.2011Emerging evidence has shown that podocyte injury and reduced specific podocyte protein expressions contribute to proteinuria in preeclampsia. We collected urine specimens from women with preeclampsia to study whether podocyte-specific protein shedding is associated with renal barrier dysfunction. Urine specimens from women with normal pregnancies and from pregnant women complicated by chronic hypertension were used for comparison. We determined soluble podocyte slit protein nephrin levels in the urine specimens. Podocalyxin, ␤ig-h3, and VEGF concentrations were also measured. We found that nephrin and podocalyxin were barely detectable in the urine specimens from normal pregnant women and from women with chronic hypertension. In preeclampsia, urinary nephrin and podocalyxin concentrations were significantly increased and highly correlated to each other, r 2 ϭ 0.595. Nephrin and podocalyxin were also correlated with urine protein concentrations. ␤ig-h3 was detected in the urine specimens from women with preeclampsia, and it is highly correlated with nephrin and podocalyxin concentrations in preeclampsia. ␤ig-h3 was undetectable in normal pregnancy and pregnancy complicated by chronic hypertension. Elevated VEGF levels were also found in women with preeclampsia compared with those of normal pregnancy and pregnancy complicated by chronic hypertension. These results provide strong evidence that podocyte protein shedding occurs in preeclampsia, and their levels are associated with proteinuria. The finding of urinary ␤ig-h3 excretion in preeclampsia suggests that increased transforming growth factor activity might also be involved in the kidney lesion in this pregnancy disorder. kidney lesion; glycoprotein shedding; TGF-␤; proteinuria; pregnancy complication NEWLY DEVELOPED HYPERTENSION and proteinuria after 20 wk of gestation are the two major clinical diagnostic criteria for preeclampsia, a hypertensive and multiple-system disorder unique to human pregnancy. Plasma protein leakage into the urine signifies renal/kidney lesions in this pregnancy disorder. Pathophysiologically, renal lesions are attributed to the glomerular endotheliosis characterized by glomerular endothelial cell swelling and subendothelial deposits of protein materials (5). Renal vasoconstriction is another contributing factor as part of the global systemic vasoconstriction in preeclampsia (9). Emerging evidence has revealed that other than glomerular endotheliosis, podocyte injury also plays a significant role in glomerular barrier dysfunction in preeclampsia (7,8,12,27,28). Supporting evidence includes 1) reduced podocyte-specific protein nephrin and synaptopodin expressions in kidney autopsy or biopsy specimens from women who had preeclampsia (7, 27); 2) detection of viable podocytes in the urine specimens ...

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Section: Discussionmentioning

confidence: 93%

Increased urinary excretion of nephrin, podocalyxin, and βig-h3 in women with preeclampsia

Wang

Zhao²,

Loyd³

et al. 2012

American Journal of Physiology-Renal Physiology

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“…Thus, it may take part in microenvironment activity on stem and leukemia cells in bone marrow. Importantly, KLF10 is a target of VHL, 25 a factor involved in the ubiquitination and degradation of the hypoxiainducible factor (HIF), which plays a central role in oxygen-mediated regulation of gene expression, particularly during hematopoiesis.…”

Section: Hoxb4 and Hoxc4 Regulate Genes Important In Various Cell Gromentioning

confidence: 99%

HOXC4 homeoprotein efficiently expands human hematopoietic stem cells and triggers similar molecular alterations as HOXB4

Auvray¹,

Delahaye²,

Pflumio³

et al. 2012

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundExpansion of hematopoietic stem cells represents an important objective for improving cell and gene therapy protocols. Retroviral transduction of the HoxB4 homeogene in mouse and human hematopoietic stem cells and hematopoietic progenitors is known to promote the cells' expansion. A safer approach consists in transferring homeobox proteins into hematopoietic stem cells taking advantage of the natural ability of homeoproteins to cross cell membranes. Thus, HOXB4 protein transfer is operative for expanding human hematopoietic cells, but such expansion needs to be improved. Design and MethodsTo that aim, we evaluated the effects of HOXC4, a protein encoded by a HOXB4 paralog gene, by co-culturing HOXC4-producing stromal cells with human CD34 + hematopoietic cells. Numbers of progenitors and stem cells were assessed by in vitro cloning assays and injection into immuno-deficient mice, respectively. We also looked for activation or inhibition of target downstream gene expression. ResultsWe show that the HOXC4 homeoprotein expands human hematopoietic immature cells by 3 to 6 times ex vivo and significantly improves the level of in vivo engraftment. Comparative transcriptome analysis of CD34 + cells subjected or not to HOXB4 or HOXC4 demonstrated that both homeoproteins regulate the same set of genes, some of which encode key hematopoietic factors and signaling molecules. Certain molecules identified herein are factors reported to be involved in stem cell fate or expansion in other models, such as MEF2C, EZH2, DBF4, DHX9, YPEL5 and Pumilio. ConclusionsThe present study may help to identify new HOX downstream key factors potentially involved in hematopoietic stem cell expansion or in leukemogenesis.

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“…For hypoxia, the cultures were grown in an atmosphere of 1% oxygen, or by adding 200 mM cobalt chloride (Sigma-Aldrich) in the culture medium. 24 The chondrogenic outcome of control and treated cultures was studied by Alcian blue staining (0.5% Alcian blue at pH 1.0). Gene expression analysis was performed both by quantitative polymerase chain reaction (Q-PCR) and by in situ hybridization.…”

Section: Micromass Culturesmentioning

confidence: 99%

“…The above-described findings, together with the observed functional interaction between hypoxia/Hif-1 signaling and big-h3 in cancer cell lines, 24 prompted us to explore if the antichondrogenic influence of big-h3 was associated with its influence on the expression of Hif-1a. As shown in Figure 6A and B, the upregulation of chondrogenic markers, including Hif-1a, observed in micromasses cultured under hypoxic conditions (1% oxygen) was prevented by addition of bIG-H3 protein in the culture medium (Fig.…”

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confidence: 99%

βig-h3 Potentiates the Profibrogenic Effect of TGFβ Signaling on Connective Tissue Progenitor Cells Through the Negative Regulation of Master Chondrogenic Genes

Lorda‐Diez

Montero

Diaz-Mendoza

et al. 2013

Tissue Engineering Part A

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Tendons and cartilage are specialized forms of connective tissues originated from common progenitor cells. Initial stages of differentiation of these tissues are characterized by the formation of cell aggregates, which share many molecular markers. Once differentiated, these cells retain considerable plasticity, and chondral metaplasia of tendon and fibrous connective tissues and eventual ossification often accompany degenerative diseases in the adult musculoskeletal system. While this fact is of great relevance for regenerative medicine and aging biology, its molecular basis remains to be elucidated. Gene expression analysis in several physiological and experimental paradigms suggests that differentiation of tendon and cartilage is regulated by a balance in the expression of chondrogenic versus tenogenic genes in the connective tissue cell precursors. Transforming growth factor b (TGFb) may function both as a profibrogenic or as a prochondrogenic factor for embryonic limb mesoderm and mesenchymal stem cell cultures, but mice that are null for TGFb 2 and 3 lack tendons. Here, we identify big-h3 as a factor downstream TGFb signaling regulated by Smad 2 and 3, which is highly expressed in the differentiating tendons and joint capsules. Furthermore, gain-and loss-of-function experiments using limb mesoderm micromass cultures show that big-h3 downregulates the expression of cartilage master genes, including Sox9, type II collagen, and Hif-1a. Positive regulation of Sox9 and type II Collagen observed in micromass cultures grown under hypoxic conditions is prevented by exogenous administration of bIG-H3, and the antichondrogenic influence of bIG-H3 is lost after Hif-1a silencing with shRNA. Collectively, our findings indicate that big-h3 promotes the fibrogenic influence of TGFb signaling, neutralizing the prochondrogenic influence of the hypoxic-inducible factor 1 activated by the hypoxic microenvironment characteristic of limb mesenchymal aggregates.

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Two novel VHL targets, TGFBI (BIGH3) and its transactivator KLF10, are up-regulated in renal clear cell carcinoma and other tumors

Cited by 52 publications

References 39 publications

Increased urinary excretion of nephrin, podocalyxin, and βig-h3 in women with preeclampsia

Increased urinary excretion of nephrin, podocalyxin, and βig-h3 in women with preeclampsia

HOXC4 homeoprotein efficiently expands human hematopoietic stem cells and triggers similar molecular alterations as HOXB4

βig-h3 Potentiates the Profibrogenic Effect of TGFβ Signaling on Connective Tissue Progenitor Cells Through the Negative Regulation of Master Chondrogenic Genes

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