TGF-beta-dependent and -independent roles of STRAP in cancer

Reiner, Jennifer Elisabeth; Datta, Pran K.

doi:10.2741/3678

Cited by 28 publications

(26 citation statements)

References 78 publications

(85 reference statements)

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“…STRAP is a serine/threonine kinase receptor–associated protein that plays a role in the cellular distribution of the survival of motor neurons (SMN) complex, important in the assembly of snRNPs (47). Deregulated expression of STRAP is associated with other human cancers, including those of the lung, colon, and breast (48, 49). …”

Section: Discussionmentioning

confidence: 99%

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

Yip¹,

Steeples²,

Repapi³

et al. 2017

Journal of Clinical Investigation

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Mutations of the splicing factor–encoding gene U2AF1 are frequent in the myelodysplastic syndromes (MDS), a myeloid malignancy, and other cancers. Patients with MDS suffer from peripheral blood cytopenias, including anemia, and an increasing percentage of bone marrow myeloblasts. We studied the impact of the common U2AF1S34F mutation on cellular function and mRNA splicing in the main cell lineages affected in MDS. We demonstrated that U2AF1S34F expression in human hematopoietic progenitors impairs erythroid differentiation and skews granulomonocytic differentiation toward granulocytes. RNA sequencing of erythroid and granulomonocytic colonies revealed that U2AF1S34F induced a higher number of cassette exon splicing events in granulomonocytic cells than in erythroid cells. U2AF1S34F altered mRNA splicing of many transcripts that were expressed in both cell types in a lineage-specific manner. In hematopoietic progenitors, the introduction of isoform changes identified in the U2AF1S34F target genes H2AFY, encoding an H2A histone variant, and STRAP, encoding serine/threonine kinase receptor–associated protein, recapitulated phenotypes associated with U2AF1S34F expression in erythroid and granulomonocytic cells, suggesting a causal link. Furthermore, we showed that isoform modulation of H2AFY and STRAP rescues the erythroid differentiation defect in U2AF1S34F MDS cells, suggesting that splicing modulators could be used therapeutically. These data have critical implications for understanding MDS phenotypic heterogeneity and support the development of therapies targeting splicing abnormalities.

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Section: Discussionmentioning

confidence: 99%

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

Yip¹,

Steeples²,

Repapi³

et al. 2017

Journal of Clinical Investigation

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“…Na,K-ATPase β 1 promoter analysis revealed among others, a putative hypoxia response element and a Smad binding domain upstream to the transcription start site. Smad transcription factors mediate TGF-β signaling by recruiting co-activators or co-repressor proteins to the nucleus to modulate target gene transcription [8, 46, 54, 55]. HIF-1α is a transcription factor well-known to be induced by hypoxia but the HIF signaling cascade can also be activated by growth factors such as TGF-β.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Na,K-ATPase β1-subunit in TGF-β2-mediated epithelial-to-mesenchymal transition in human retinal pigmented epithelial cells

Mony

Lee

Harper

et al. 2013

Experimental Eye Research

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Proliferative vitreo retinopathy (PVR) is associated with extracellular matrix membrane (ECM) formation on the neural retina and disruption of the multilayered retinal architecture leading to distorted vision and blindness. During disease progression in PVR, retinal pigmented epithelial cells (RPE) lose cell-cell adhesion, undergo epithelial-to-mesenchymal transition (EMT), and deposit ECM leading to tissue fibrosis. The EMT process is mediated via exposure to vitreous cytokines and growth factors such as TGF-β2. Previous studies have shown that Na,K-ATPase is required for maintaining a normal polarized epithelial phenotype and that decreased Na,K-ATPase function and subunit levels are associated with TGF-β1-mediated EMT in kidney cells. In contrast to the basolateral localization of Na,K-ATPase in most epithelia, including kidney, Na,K-ATPase is found on the apical membrane in RPE cells. We now show that EMT is also associated with altered Na,K-ATPase expression in RPE cells. TGF-β2 treatment of ARPE-19 cells resulted in a time-dependent decrease in Na,K-ATPase β1 mRNA and protein levels while Na,K-ATPase α1 levels, Na,K-ATPase activity, and intracellular sodium levels remained largely unchanged. In TGF-β2–treated cells reduced Na,K-ATPase β1 mRNA inversely correlated with HIF-1α levels and analysis of the Na,K-ATPase β1 promoter revealed a putative hypoxia response element (HRE). HIF-1α bound to the Na,K-ATPase β1 promoter and inhibiting the activity of HIF-1α blocked the TGF-β2 mediated Na,K-ATPase β1 decrease suggesting that HIF-1α plays a potential role in Na,K-ATPase β1 regulation during EMT in RPE cells. Furthermore, knockdown of Na,K-ATPase β1 in ARPE-19 cells was associated with a change in cell morphology from epithelial to mesenchymal and induction of EMT markers such as α-smooth muscle actin and fibronectin, suggesting that loss of Na,K-ATPase β1 is a potential contributor to TGF-β2-mediated EMT in RPE cells.

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“…Although the specific biological function of STRAP varies according to its binding partner, STRAP binding to these proteins generally promotes signaling pathways and processes that are frequently associated with tumorigenesis [25]. Previous studies on c-Jun indicate that its expression is important for cellular proliferation as c-Jun knockout MEFs exhibit a significant delay in cell cycle progression [6,8].…”

Section: Discussionmentioning

confidence: 99%

STRAP regulates c-Jun ubiquitin-mediated proteolysis and cellular proliferation

Reiner

Kashikar

et al. 2011

Biochemical and Biophysical Research Communications

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STRAP is a ubiquitious WD40 protein that has been implicated in tumorigenesis. Previous studies suggest that STRAP imparts oncogenic characteristics to cells by promoting ERK and pRb phosphorylation. While these findings suggest that STRAP can activate mitogenic signaling pathways, the effects of STRAP on other MAPK pathways have not been investigated. Herein, we report that STRAP regulates the expression of the c-Jun proto-oncogene in mouse embryonic fibroblasts. Loss of STRAP expression results in reduced phospho-c-Jun and total c-Jun but does not significantly reduce the level of two other early response genes, c-Myc and c-Fos. STRAP knockout also decreases expression of the AP-1 target gene, cyclin D1, which is accompanied by a reduction in cell growth. No significant differences in JNK activity or basal c-Jun mRNA levels were observed between wild type and STRAP null fibroblasts. However, proteosomal inhibition markedly increases c-Jun expression in STRAP knockout MEFs and STRAP over-expression decreases the ubiquitylation of c-Jun in 293T cells. Loss of STRAP accelerates c-Jun turnover in fibroblasts and ectopic over-expression of STRAP in STRAP null fibroblasts increases c-Jun expression. Collectively, our findings indicate that STRAP regulates c-Jun stability by decreasing the ubiquitylation and degradation of c-Jun.

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TGF-beta-dependent and -independent roles of STRAP in cancer

Cited by 28 publications

References 78 publications

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

Regulation of Na,K-ATPase β1-subunit in TGF-β2-mediated epithelial-to-mesenchymal transition in human retinal pigmented epithelial cells

STRAP regulates c-Jun ubiquitin-mediated proteolysis and cellular proliferation

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