Oncogenic serine-threonine kinase receptor-associated protein modulates the function of ewing sarcoma protein through a novel mechanism

Govindaraj Anumanthan, Sunil Krishna Halder, David B. Friedman, Pran K. Datta

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Although much is known about the oncogenic functions of chimeric Ewing sarcoma (EWS) fusion proteins that result from chromosomal translocations, the cellular role of the normal EWS protein is not well characterized. We have previously identified a WD domain-containing protein, serine-threonine kinase receptor-associated protein (STRAP), which inhibits transforming growth factor β (TGF-β) signaling through interaction with receptors and Smad7 and promotes growth and enhances tumorigenicity. Here, we report the interaction between STRAP and EWS using matrix-assisted laser desorption/ionization, time-of-flight and tandem mass spectrometry. Although STRAP is localized in both cytoplasm and nucleus, nuclear STRAP colocalizes and associates specifically with EWS in the nucleus through its NH2 and COOH termini. We have found that normal EWS protein is up-regulated in human cancers, which correlates with the up-regulation of STRAP in 71% of colorectal cancers and 54% of lung cancers, suggesting a cooperative role of these two proteins in human cancers. TGF-β has no effect on STRAP and EWS interaction. However, EWS, like STRAP, attenuates TGF-β-dependent transcription. STRAP inhibits EWS-dependent p300-mediated transactivation of EWS target genes, such as ApoCIII and c-fos, in a TGF-β-independent manner. Interestingly, we have shown that STRAP blocks the interaction between EWS and p300, whereas the complex formation between STRAP and EWS is not affected by p300. These results suggest that STRAP inhibits the transactivation function of EWS by displacing p300 from the functional transcriptional complex. Thus, this study provides a novel TGF-β- independent function of STRAP and describes a mechanism by which STRAP regulates the function of oncogenic EWS protein.

Original languageEnglish (US)
Pages (from-to)10824-10832
Number of pages9
JournalCancer Research
Volume66
Issue number22
DOIs
StatePublished - Nov 15 2006

Fingerprint

Ewing's Sarcoma
Protein-Serine-Threonine Kinases
Proteins
Transforming Growth Factors
Transcriptional Activation
Lung Neoplasms
Genetic Translocation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Oncogenic serine-threonine kinase receptor-associated protein modulates the function of ewing sarcoma protein through a novel mechanism. / Anumanthan, Govindaraj; Halder, Sunil Krishna; Friedman, David B.; Datta, Pran K.

In: Cancer Research, Vol. 66, No. 22, 15.11.2006, p. 10824-10832.

Research output: Contribution to journalArticle

Anumanthan, Govindaraj ; Halder, Sunil Krishna ; Friedman, David B. ; Datta, Pran K. / Oncogenic serine-threonine kinase receptor-associated protein modulates the function of ewing sarcoma protein through a novel mechanism. In: Cancer Research. 2006 ; Vol. 66, No. 22. pp. 10824-10832.
@article{359f3d0486dc49c1a994fd3b8276fe43,
title = "Oncogenic serine-threonine kinase receptor-associated protein modulates the function of ewing sarcoma protein through a novel mechanism",
abstract = "Although much is known about the oncogenic functions of chimeric Ewing sarcoma (EWS) fusion proteins that result from chromosomal translocations, the cellular role of the normal EWS protein is not well characterized. We have previously identified a WD domain-containing protein, serine-threonine kinase receptor-associated protein (STRAP), which inhibits transforming growth factor β (TGF-β) signaling through interaction with receptors and Smad7 and promotes growth and enhances tumorigenicity. Here, we report the interaction between STRAP and EWS using matrix-assisted laser desorption/ionization, time-of-flight and tandem mass spectrometry. Although STRAP is localized in both cytoplasm and nucleus, nuclear STRAP colocalizes and associates specifically with EWS in the nucleus through its NH2 and COOH termini. We have found that normal EWS protein is up-regulated in human cancers, which correlates with the up-regulation of STRAP in 71{\%} of colorectal cancers and 54{\%} of lung cancers, suggesting a cooperative role of these two proteins in human cancers. TGF-β has no effect on STRAP and EWS interaction. However, EWS, like STRAP, attenuates TGF-β-dependent transcription. STRAP inhibits EWS-dependent p300-mediated transactivation of EWS target genes, such as ApoCIII and c-fos, in a TGF-β-independent manner. Interestingly, we have shown that STRAP blocks the interaction between EWS and p300, whereas the complex formation between STRAP and EWS is not affected by p300. These results suggest that STRAP inhibits the transactivation function of EWS by displacing p300 from the functional transcriptional complex. Thus, this study provides a novel TGF-β- independent function of STRAP and describes a mechanism by which STRAP regulates the function of oncogenic EWS protein.",
author = "Govindaraj Anumanthan and Halder, {Sunil Krishna} and Friedman, {David B.} and Datta, {Pran K.}",
year = "2006",
month = "11",
day = "15",
doi = "10.1158/0008-5472.CAN-06-1599",
language = "English (US)",
volume = "66",
pages = "10824--10832",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "22",

}

TY - JOUR

T1 - Oncogenic serine-threonine kinase receptor-associated protein modulates the function of ewing sarcoma protein through a novel mechanism

AU - Anumanthan, Govindaraj

AU - Halder, Sunil Krishna

AU - Friedman, David B.

AU - Datta, Pran K.

PY - 2006/11/15

Y1 - 2006/11/15

N2 - Although much is known about the oncogenic functions of chimeric Ewing sarcoma (EWS) fusion proteins that result from chromosomal translocations, the cellular role of the normal EWS protein is not well characterized. We have previously identified a WD domain-containing protein, serine-threonine kinase receptor-associated protein (STRAP), which inhibits transforming growth factor β (TGF-β) signaling through interaction with receptors and Smad7 and promotes growth and enhances tumorigenicity. Here, we report the interaction between STRAP and EWS using matrix-assisted laser desorption/ionization, time-of-flight and tandem mass spectrometry. Although STRAP is localized in both cytoplasm and nucleus, nuclear STRAP colocalizes and associates specifically with EWS in the nucleus through its NH2 and COOH termini. We have found that normal EWS protein is up-regulated in human cancers, which correlates with the up-regulation of STRAP in 71% of colorectal cancers and 54% of lung cancers, suggesting a cooperative role of these two proteins in human cancers. TGF-β has no effect on STRAP and EWS interaction. However, EWS, like STRAP, attenuates TGF-β-dependent transcription. STRAP inhibits EWS-dependent p300-mediated transactivation of EWS target genes, such as ApoCIII and c-fos, in a TGF-β-independent manner. Interestingly, we have shown that STRAP blocks the interaction between EWS and p300, whereas the complex formation between STRAP and EWS is not affected by p300. These results suggest that STRAP inhibits the transactivation function of EWS by displacing p300 from the functional transcriptional complex. Thus, this study provides a novel TGF-β- independent function of STRAP and describes a mechanism by which STRAP regulates the function of oncogenic EWS protein.

AB - Although much is known about the oncogenic functions of chimeric Ewing sarcoma (EWS) fusion proteins that result from chromosomal translocations, the cellular role of the normal EWS protein is not well characterized. We have previously identified a WD domain-containing protein, serine-threonine kinase receptor-associated protein (STRAP), which inhibits transforming growth factor β (TGF-β) signaling through interaction with receptors and Smad7 and promotes growth and enhances tumorigenicity. Here, we report the interaction between STRAP and EWS using matrix-assisted laser desorption/ionization, time-of-flight and tandem mass spectrometry. Although STRAP is localized in both cytoplasm and nucleus, nuclear STRAP colocalizes and associates specifically with EWS in the nucleus through its NH2 and COOH termini. We have found that normal EWS protein is up-regulated in human cancers, which correlates with the up-regulation of STRAP in 71% of colorectal cancers and 54% of lung cancers, suggesting a cooperative role of these two proteins in human cancers. TGF-β has no effect on STRAP and EWS interaction. However, EWS, like STRAP, attenuates TGF-β-dependent transcription. STRAP inhibits EWS-dependent p300-mediated transactivation of EWS target genes, such as ApoCIII and c-fos, in a TGF-β-independent manner. Interestingly, we have shown that STRAP blocks the interaction between EWS and p300, whereas the complex formation between STRAP and EWS is not affected by p300. These results suggest that STRAP inhibits the transactivation function of EWS by displacing p300 from the functional transcriptional complex. Thus, this study provides a novel TGF-β- independent function of STRAP and describes a mechanism by which STRAP regulates the function of oncogenic EWS protein.

UR - http://www.scopus.com/inward/record.url?scp=33845333409&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33845333409&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-06-1599

DO - 10.1158/0008-5472.CAN-06-1599

M3 - Article

C2 - 17108118

AN - SCOPUS:33845333409

VL - 66

SP - 10824

EP - 10832

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 22

ER -