Antagonistic roles of four SR proteins in the biosynthesis of alternatively spliced tissue factor transcripts in monocytic cells

Chandradas, Sajiv; Deikus, Gintaras; Tardos, Jonathan G.; Bogdanov, Vladimir Y.

doi:10.1189/jlb.0409252

Cited by 23 publications

(32 citation statements)

References 23 publications

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“…Both TF isoforms are known to modulate cancer cell migration, metastasis, and invasiveness (2,20,32 ). In 2011, we found that increased amounts of asTF in cell culture media induced migration of THP-1 leukemia cells in vitro (10 ).…”

Section: The Role Of Tf Isoforms In Cancer Cell Migration Tumor Metamentioning

confidence: 92%

“…In 2010, Chandradas et al showed that the SR proteins SRp40, SC35, ASF/SF2, and SRp55 modulate TF isoform expression in the human monocytic leukemia cell line THP-1. They found that binding of SRp40 and SC35 to regulatory motifs in the TF pre-mRNA sequence increased the generation of asTF (20 ). Moreover, they depicted binding of ASF/SF2 and SRp55 to regulatory premRNA sites to facilitate flTF expression in THP-1 cells (20 ).…”

Section: Tf Isoform Expression In Cancermentioning

confidence: 98%

“…They found that binding of SRp40 and SC35 to regulatory motifs in the TF pre-mRNA sequence increased the generation of asTF (20 ). Moreover, they depicted binding of ASF/SF2 and SRp55 to regulatory premRNA sites to facilitate flTF expression in THP-1 cells (20 ). The authors suggested that SR protein-mediated control of asTF and flTF generation could potentially affect cancer-related thrombogenicity and angiogenesis (20 ).…”

Section: Tf Isoform Expression In Cancermentioning

confidence: 99%

“…Moreover, they depicted binding of ASF/SF2 and SRp55 to regulatory premRNA sites to facilitate flTF expression in THP-1 cells (20 ). The authors suggested that SR protein-mediated control of asTF and flTF generation could potentially affect cancer-related thrombogenicity and angiogenesis (20 ). Recently, we demonstrated hypoxia to induce asTF and flTF expression in A549 lung cancer cells (2 ).…”

Section: Tf Isoform Expression In Cancermentioning

confidence: 99%

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Tissue Factor: A Conventional or Alternative Target in Cancer Therapy

2016

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BACKGROUND:Tissue factor (TF) is an evolutionary conserved glycoprotein that plays an important role in the pathogenesis of cancer. TF is expressed in 2 naturally occurring protein isoforms, membrane-bound full-length (fl)TF and soluble alternatively spliced (as)TF. Both isoforms have been shown to affect a variety of pathophysiologically relevant functions, such as tumor-associated angiogenesis, thrombogenicity, tumor growth, and metastasis. Therefore, targeting TF either by direct inhibition or indirectly, i.e., on a posttranscriptional level, offers a novel therapeutic option for cancer treatment.CONTENT: In this review we summarize the latest findings regarding the role of TF and its isoforms in cancer biology. Moreover, we briefly depict and discuss the therapeutic potential of direct and/or indirect inhibition of TF activity and expression for the treatment of cancer.

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Section: The Role Of Tf Isoforms In Cancer Cell Migration Tumor Metamentioning

confidence: 92%

Section: Tf Isoform Expression In Cancermentioning

confidence: 98%

Section: Tf Isoform Expression In Cancermentioning

confidence: 99%

Section: Tf Isoform Expression In Cancermentioning

confidence: 99%

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Tissue Factor: A Conventional or Alternative Target in Cancer Therapy

2016

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“…Regulated splicing of TF pre-mRNA in human monocytes is controlled by several serine-rich (SR) proteins, including ASF/SF2 and SRp55 (17,18). Expression of SR proteins is frequently perturbed in BrCa tumors (2), and it is thus plausible that the relative abundance of flTF and asTF is also altered in BrCa.…”

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confidence: 99%

Alternatively spliced tissue factor promotes breast cancer growth in a β1 integrin-dependent manner

Kocatürk¹,

Berg²,

Tieken³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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126

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Full-length tissue factor (flTF), the coagulation initiator, is overexpressed in breast cancer (BrCa), but associations between flTF expression and clinical outcome remain controversial. It is currently not known whether the soluble alternatively spliced TF form (asTF) is expressed in BrCa or impacts BrCa progression. We are unique in reporting that asTF, but not flTF, strongly associates with both tumor size and grade, and induces BrCa cell proliferation by binding to β1 integrins. asTF promotes oncogenic gene expression, anchorage-independent growth, and strongly up-regulates tumor expansion in a luminal BrCa model. In basal BrCa cells that constitutively express both TF isoforms, asTF blockade reduces tumor growth and proliferation in vivo. We propose that asTF plays a major role in BrCa progression acting as an autocrine factor that promotes tumor progression. Targeting asTF may comprise a previously unexplored therapeutic strategy in BrCa that stems tumor growth, yet does not impair normal hemostasis.regulated pre-mRNA processing | outside-in signaling I n breast cancer (BrCa), proteins that modulate splicing events such as ASF/SF2 and SR(Serine/Arginine-rich)p55, are frequently up-regulated and contribute to cell transformation (1, 2). BrCa cells exhibit specific alternative splicing signatures that were proposed as potential prognostic factors in BrCa (3). Alternative splicing of proteins, such as spleen tyrosine kinase (Syk), p53, phosphatase and tensin homolog (PTEN), chemokine (C-X-C motif) receptor 3 (CXCR3), and ras-related C3 botulinum toxin substrate 1 (Rac1) impacts BrCa cell behavior and therefore, disease progression (4-8).Full-length tissue factor (flTF) is the initiator of blood coagulation (9). Following vascular damage, flTF binds its ligand FVII(a), which triggers clot formation. Aside from subendothelial tissues, flTF is also abundant on cancer cells (9) and fuels tumor progression by modulating integrin α3β1 function, cell migration (10), and FVIIa-dependent protease activated receptor (PAR)2 activation, but flTF-β1 integrin complexation enhances PAR2 activation (11). flTF-dependent PAR2 activation results in the production of VEGF, CXCL1, and IL-8, thus promoting the angiogenic switch and consequently, tumor growth in vivo (10, 11).Alternative splicing of TF pre-mRNA results in the deletion of exon 5 and thus a frameshift in exon 6, yielding a transmembrane domain-lacking isoform that can be secreted (12). Human and murine alternatively spliced TF (asTF) contain novel C termini with poor homology to one another or any other protein, and the murine asTF C terminus is longer than that of human asTF (12,13). High expression of asTF in tumor cell lines suggests a role in tumor progression (10,14). Subcutaneous growth of pancreatic cancer cells overexpressing asTF results in larger and more vascularized tumors (15). We recently discovered that asTF induces angiogenesis, independent of PAR2 activation, by acting as an integrin ligand (16). Thus, flTF and asTF facilitate cellular signaling via ...

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The role of tissue factor isoforms in cancer biology

Leppert

Eisenreich

2014

Int. J. Cancer

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Tissue Factor (TF) is an evolutionary conserved glycoprotein, which is of immense importance for a variety of biologic processes. TF is expressed in two naturally occurring protein isoforms, membrane-bound "full-length" (fl)TF and soluble alternatively spliced (as)TF. The TF isoform expression is differentially modulated on post-transcriptional level via regulatory factors, such as serine/arginine-rich (SR) proteins, SR protein kinases and micro (mi)RNAs. Both isoforms mediate a variety of physiologic-and pathophysiologic-relevant functions, such as thrombogenicity, angiogenesis, cell signaling, tumor cell proliferation and metastasis. In this review, we will depict the main mechanisms regulating the TF isoform expression in cancer and under other pathophysiologic-relevant conditions. Moreover, we will summarize and discuss the latest findings regarding the role of TF and its isoforms in cancer biology.Tissue factor (TF) is a glycoprotein and an evolutionary conserved member of the Class II cytokine receptor family, which was found in different species, such as human, mouse, rat, fish as well as in Drosophila melanogaster and mosquitos. 1-3 TF is expressed in two natural occurring protein isoforms, full-length (fl)TF and alternatively spliced (as)TF. [4][5][6] In human, flTF consists of a short intracellular domain (21 amino acids), a transmembrane domain (23 amino acids) and an extracellular domain (219 amino acids). 7 flTF is anchored to the cell membrane. 7,8 The primary function of flTF is the initiation of the blood coagulation cascade. 2,7,8 Beside this, flTF plays an important role in a variety of other biological processes, such as protease-activated receptor (PAR-)2-mediated cell signaling and tumor progression. 2,9,10 Due to alternative splicing the fifth exon of the primary TF transcript is excluded. 5,7 Translation of this messenger (m)RNA splice variant leads to the generation of asTF on protein level. asTF lacks the transmembrane domain and is therefore soluble. 7 Compared with flTF, asTF exhibits low prothrombogenic potential. 4,7,8 However, this isoform was recently linked more closely to angiogenesis, survival and cell growth. 3,[11][12][13][14] Post-transcriptional expression control regulate a variety of biologic functions, such as tumor cell invasion, metastasis and angiogenesis in cancer as well as in other settings. [15][16][17][18] Two major mechanisms modulate post-transcriptional expression: micro (mi)RNAs and alternative splicing processes. 16 In this review, we will discuss the latest findings regarding the impact of TF and its isoforms on cancer biology with special focus on pathophysiologic-relevant functions, such as thrombogenicity, tumor cell growth and angiogenesis. Moreover, we will shed light on the mechanisms regulating the TF isoform expression in cancer and under other pathophysiologic-relevant conditions. Cancer-Related Stimulation of TF ExpressionSeveral stimuli, such as hypoxia, vascular endothelial growth factor (VEGF) and the proinflammatory cytokine tumor necrosis fact...

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Antagonistic roles of four SR proteins in the biosynthesis of alternatively spliced tissue factor transcripts in monocytic cells

Cited by 23 publications

References 23 publications

Tissue Factor: A Conventional or Alternative Target in Cancer Therapy

Tissue Factor: A Conventional or Alternative Target in Cancer Therapy

Alternatively spliced tissue factor promotes breast cancer growth in a β1 integrin-dependent manner

The role of tissue factor isoforms in cancer biology

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