A transforming growth factor-β receptor-interacting protein frequently mutated in human ovarian cancer

Wei Ding, Qian Tang, Virginia Espina, Lance A. Liotta, David Mauger, Kathleen Mulder

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Ovarian carcinomas, particularly recurrent forms, are frequently resistant to transforming growth factor-β (TGF-β)-mediated growth inhibition. However, mutations in the TGF-β receptor I and receptor II (TβR-I and TβR-II) genes have only been reported in a minority of ovarian carcinomas, suggesting that alterations in TGF-β-signaling components may play an important role in the loss of TGF-β responsiveness. Using laser-capture microdissection and nested reverse-transcription-PCR, we found that km23, which interacts with the TGF-β receptor complex, is altered at a high frequency in human ovarian cancer patients. A novel form of km23, missing exon 3 (Δexon3-km23), was found in 2 of 19 tumor tissues from patients with ovarian cancer. In addition to this alteration, a stop codon mutation (TAA → CAC) was detected in two patients. This alteration results in an elongated protein, encoding 107-amino-acid residues (Δl07km23), instead of the wild-type 96-amino-acid form of km23. Furthermore, five missense mutations (T38I, S55G, T56S, I89V, and V90A) were detected in four patients, providing a total alteration rate of 42.1% (8 of 19 cases) in ovarian cancer. No km23 alterations were detected in 15 normal tissues. Such a high alteration rate in ovarian cancer suggests that km23 may play an important role in either TGF-β resistance or tumor progression in this disease. In keeping with these findings, the functional studies described herein indicate that both the Δexon3-km23 and S55G/I89V-km23 mutants displayed a disruption in binding to the dynein intermediate chain in vivo, suggesting a defect in cargo recruitment to the dynein motor complex. In addition, the Δexon3-km23 resulted in an inhibition of TGF-β-dependent transcriptional activation of both the p3TP-lux and activin responsive element reporters. Collectively, our results suggest that km23 alterations found in ovarian cancer patients result in altered dynein motor complex formation and/or aberrant transcriptional regulation by TGF-β.

Original languageEnglish (US)
Pages (from-to)6526-6533
Number of pages8
JournalCancer Research
Volume65
Issue number15
DOIs
StatePublished - Aug 1 2005

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Receptor-Interacting Protein Serine-Threonine Kinases
Growth Factor Receptors
Transforming Growth Factors
Ovarian Neoplasms
Dyneins
Laser Capture Microdissection
Carcinoma
Amino Acids
Activins
Mutation
Terminator Codon
Missense Mutation
Transcriptional Activation
Reverse Transcription
Disease Progression
Exons
Neoplasms
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "A transforming growth factor-β receptor-interacting protein frequently mutated in human ovarian cancer",
abstract = "Ovarian carcinomas, particularly recurrent forms, are frequently resistant to transforming growth factor-β (TGF-β)-mediated growth inhibition. However, mutations in the TGF-β receptor I and receptor II (TβR-I and TβR-II) genes have only been reported in a minority of ovarian carcinomas, suggesting that alterations in TGF-β-signaling components may play an important role in the loss of TGF-β responsiveness. Using laser-capture microdissection and nested reverse-transcription-PCR, we found that km23, which interacts with the TGF-β receptor complex, is altered at a high frequency in human ovarian cancer patients. A novel form of km23, missing exon 3 (Δexon3-km23), was found in 2 of 19 tumor tissues from patients with ovarian cancer. In addition to this alteration, a stop codon mutation (TAA → CAC) was detected in two patients. This alteration results in an elongated protein, encoding 107-amino-acid residues (Δl07km23), instead of the wild-type 96-amino-acid form of km23. Furthermore, five missense mutations (T38I, S55G, T56S, I89V, and V90A) were detected in four patients, providing a total alteration rate of 42.1{\%} (8 of 19 cases) in ovarian cancer. No km23 alterations were detected in 15 normal tissues. Such a high alteration rate in ovarian cancer suggests that km23 may play an important role in either TGF-β resistance or tumor progression in this disease. In keeping with these findings, the functional studies described herein indicate that both the Δexon3-km23 and S55G/I89V-km23 mutants displayed a disruption in binding to the dynein intermediate chain in vivo, suggesting a defect in cargo recruitment to the dynein motor complex. In addition, the Δexon3-km23 resulted in an inhibition of TGF-β-dependent transcriptional activation of both the p3TP-lux and activin responsive element reporters. Collectively, our results suggest that km23 alterations found in ovarian cancer patients result in altered dynein motor complex formation and/or aberrant transcriptional regulation by TGF-β.",
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A transforming growth factor-β receptor-interacting protein frequently mutated in human ovarian cancer. / Ding, Wei; Tang, Qian; Espina, Virginia; Liotta, Lance A.; Mauger, David; Mulder, Kathleen.

In: Cancer Research, Vol. 65, No. 15, 01.08.2005, p. 6526-6533.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A transforming growth factor-β receptor-interacting protein frequently mutated in human ovarian cancer

AU - Ding, Wei

AU - Tang, Qian

AU - Espina, Virginia

AU - Liotta, Lance A.

AU - Mauger, David

AU - Mulder, Kathleen

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N2 - Ovarian carcinomas, particularly recurrent forms, are frequently resistant to transforming growth factor-β (TGF-β)-mediated growth inhibition. However, mutations in the TGF-β receptor I and receptor II (TβR-I and TβR-II) genes have only been reported in a minority of ovarian carcinomas, suggesting that alterations in TGF-β-signaling components may play an important role in the loss of TGF-β responsiveness. Using laser-capture microdissection and nested reverse-transcription-PCR, we found that km23, which interacts with the TGF-β receptor complex, is altered at a high frequency in human ovarian cancer patients. A novel form of km23, missing exon 3 (Δexon3-km23), was found in 2 of 19 tumor tissues from patients with ovarian cancer. In addition to this alteration, a stop codon mutation (TAA → CAC) was detected in two patients. This alteration results in an elongated protein, encoding 107-amino-acid residues (Δl07km23), instead of the wild-type 96-amino-acid form of km23. Furthermore, five missense mutations (T38I, S55G, T56S, I89V, and V90A) were detected in four patients, providing a total alteration rate of 42.1% (8 of 19 cases) in ovarian cancer. No km23 alterations were detected in 15 normal tissues. Such a high alteration rate in ovarian cancer suggests that km23 may play an important role in either TGF-β resistance or tumor progression in this disease. In keeping with these findings, the functional studies described herein indicate that both the Δexon3-km23 and S55G/I89V-km23 mutants displayed a disruption in binding to the dynein intermediate chain in vivo, suggesting a defect in cargo recruitment to the dynein motor complex. In addition, the Δexon3-km23 resulted in an inhibition of TGF-β-dependent transcriptional activation of both the p3TP-lux and activin responsive element reporters. Collectively, our results suggest that km23 alterations found in ovarian cancer patients result in altered dynein motor complex formation and/or aberrant transcriptional regulation by TGF-β.

AB - Ovarian carcinomas, particularly recurrent forms, are frequently resistant to transforming growth factor-β (TGF-β)-mediated growth inhibition. However, mutations in the TGF-β receptor I and receptor II (TβR-I and TβR-II) genes have only been reported in a minority of ovarian carcinomas, suggesting that alterations in TGF-β-signaling components may play an important role in the loss of TGF-β responsiveness. Using laser-capture microdissection and nested reverse-transcription-PCR, we found that km23, which interacts with the TGF-β receptor complex, is altered at a high frequency in human ovarian cancer patients. A novel form of km23, missing exon 3 (Δexon3-km23), was found in 2 of 19 tumor tissues from patients with ovarian cancer. In addition to this alteration, a stop codon mutation (TAA → CAC) was detected in two patients. This alteration results in an elongated protein, encoding 107-amino-acid residues (Δl07km23), instead of the wild-type 96-amino-acid form of km23. Furthermore, five missense mutations (T38I, S55G, T56S, I89V, and V90A) were detected in four patients, providing a total alteration rate of 42.1% (8 of 19 cases) in ovarian cancer. No km23 alterations were detected in 15 normal tissues. Such a high alteration rate in ovarian cancer suggests that km23 may play an important role in either TGF-β resistance or tumor progression in this disease. In keeping with these findings, the functional studies described herein indicate that both the Δexon3-km23 and S55G/I89V-km23 mutants displayed a disruption in binding to the dynein intermediate chain in vivo, suggesting a defect in cargo recruitment to the dynein motor complex. In addition, the Δexon3-km23 resulted in an inhibition of TGF-β-dependent transcriptional activation of both the p3TP-lux and activin responsive element reporters. Collectively, our results suggest that km23 alterations found in ovarian cancer patients result in altered dynein motor complex formation and/or aberrant transcriptional regulation by TGF-β.

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