This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ding, W. Articles by Mulder, K. M. Search for Related Content PubMed PubMed Citation Articles by Ding, W. Articles by Mulder, K. M.

A Transforming Growth Factor-ß Receptor–Interacting Protein Frequently Mutated in Human Ovarian Cancer

Departments of ¹ Pharmacology and ² Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania and ³ National Cancer Institute Clinical Proteomics Program, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Kathleen M. Mulder, Department of Pharmacology-MC H078, Pennsylvania State College of Medicine, 500 University Drive, Hershey, PA 17033. Phone: 717-531-6789; Fax: 717-531-5013; E-mail: kmm15{at}psu.edu.

Ovarian carcinomas, particularly recurrent forms, are frequently resistant to transforming growth factor-ß (TGF-ß)–mediated growth inhibition. However, mutations in the TGF-ß receptor I and receptor II (TßR-I and TßR-II) genes have only been reported in a minority of ovarian carcinomas, suggesting that alterations in TGF-ß–signaling components may play an important role in the loss of TGF-ß responsiveness. Using laser-capture microdissection and nested reverse-transcription-PCR, we found that km23, which interacts with the TGF-ß receptor complex, is altered at a high frequency in human ovarian cancer patients. A novel form of km23, missing exon 3 (exon3-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 (107km23), 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-ß resistance or tumor progression in this disease. In keeping with these findings, the functional studies described herein indicate that both the exon3-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 exon3-km23 resulted in an inhibition of TGF-ß–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-ß.

This article has been cited by other articles:

				Q. Jin, W. Ding, and K. M. Mulder Requirement for the Dynein Light Chain km23-1 in a Smad2-dependent Transforming Growth Factor-beta Signaling Pathway J. Biol. Chem., June 29, 2007; 282(26): 19122 - 19132. [Abstract] [Full Text] [PDF]

				Q. Meng, A. Lux, A. Holloschi, J. Li, J. M. X. Hughes, T. Foerg, J. E. G. McCarthy, A. M. Heagerty, P. Kioschis, M. Hafner, et al. Identification of Tctex2beta, a Novel Dynein Light Chain Family Member That Interacts with Different Transforming Growth Factor-beta Receptors J. Biol. Chem., December 1, 2006; 281(48): 37069 - 37080. [Abstract] [Full Text] [PDF]

				I. G. Campbell, W. A. Phillips, and D. Y.H. Choong Genetic and Epigenetic Analysis of the Putative Tumor Suppressor km23 in Primary Ovarian, Breast, and Colorectal Cancers. Clin. Cancer Res., June 15, 2006; 12(12): 3713 - 3715. [Abstract] [Full Text] [PDF]