This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Liu, L. Articles by McKeehan, W. L. Search for Related Content PubMed PubMed Citation Articles by Liu, L. Articles by McKeehan, W. L.

Specificity of the Methylation-Suppressed A Isoform of Candidate Tumor Suppressor RASSF1 for Microtubule Hyperstabilization Is Determined by Cell Death Inducer C19ORF5

Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas

Requests for reprints: Wallace L. McKeehan, Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, 2121 W. Holcombe Boulevard, Houston, TX 77030. Phone: 713-677-7522; Fax: 713-677-7512; E-mail: wmckeeha{at}ibt.tamu.edu.

Isoform-specific epigenetic silencing of RASSF1A (3p21.3) by promoter-specific CpG island hypermethylation occurs at high frequency in human tumors, whereas the closely related product of the same gene, RASSF1C, continues to be expressed. Both isoforms in isolation exhibit tumor suppressor properties and we show here similar cellular locations on mitochondria and microtubules, paclitaxel-like microtubule hyperstabilization, disruption of mitosis, and interaction with C19ORF5. We show both have identical but distinct sequence domains for microtubule association and hyperstabilization. C19ORF5 is a hyperstabilized microtubule-specific binding protein of which accumulation causes mitochondrial aggregation and cell death. We report herein that when A or C isoforms of RASSF1 are coexpressed with C19ORF5, the unique N-terminal sequence of RASSF1C prevents it from hyperstabilizing microtubules. This confers specificity on RASSF1A in microtubule hyperstabilization and accumulation of C19ORF5 on microtubules and could underlie a specific effect of hypermethylation-suppressed RASSF1A in tumor suppression.

Key Words: aneuploidy • apoptosis • C19ORF5 • genetic instability • hyperstabilization • LRPPRC • microtubule-associated protein 1B • microtubules • mitochondria • mitotic spindle • paclitaxel • RASSF1A • RASSF1C • RASSF1B • VCY2IP1

This article has been cited by other articles:

				C. J. Foley, H. Freedman, S. L. Choo, C. Onyskiw, N. Y. Fu, V. C. Yu, J. Tuszynski, J. C. Pratt, and S. Baksh Dynamics of RASSF1A/MOAP-1 Association with Death Receptors Mol. Cell. Biol., July 15, 2008; 28(14): 4520 - 4535. [Abstract] [Full Text] [PDF]

				B. Gao, X.-J. Xie, C. Huang, D. S. Shames, T. T-L. Chen, C. M. Lewis, A. Bian, B. Zhang, O. I. Olopade, J. E. Garber, et al. RASSF1A Polymorphism A133S Is Associated with Early Onset Breast Cancer in BRCA1/2 Mutation Carriers Cancer Res., January 1, 2008; 68(1): 22 - 25. [Abstract] [Full Text] [PDF]

				A. Dallol, W. N. Cooper, F. Al-Mulla, A. Agathanggelou, E. R. Maher, and F. Latif Depletion of the Ras Association Domain Family 1, Isoform A-Associated Novel Microtubule-Associated Protein, C19ORF5/MAP1S, Causes Mitotic Abnormalities Cancer Res., January 15, 2007; 67(2): 492 - 500. [Abstract] [Full Text] [PDF]

				K. O. Tan, N. Y. Fu, S. K. Sukumaran, S.-L. Chan, J. H. Kang, K. L. Poon, B. S. Chen, and V. C. Yu MAP-1 is a mitochondrial effector of Bax PNAS, October 11, 2005; 102(41): 14623 - 14628. [Abstract] [Full Text] [PDF]

				L. Liu, A. Vo, G. Liu, and W. L. McKeehan Distinct Structural Domains within C19ORF5 Support Association with Stabilized Microtubules and Mitochondrial Aggregation and Genome Destruction Cancer Res., May 15, 2005; 65(10): 4191 - 4201. [Abstract] [Full Text] [PDF]