Inhibition of G1 to S Phase Progression by a Novel Zinc Finger Protein P58 at P-bodies

Abstract

We recently reported the translocation of the immunoglobulin (Ig) light chain κ locus gene with a possible tumor suppressor gene, TFL, in transformed follicular lymphoma. However, the functional significance in cell transformation remains to be elucidated. Here, we first identified two gene products, P58 and P36, derived by alternative splicing. The expressionwasprominent in normal human lymphocytes but defective in some leukemia/lymphoma cell lines. Overexpression of either protein in a mouse pro-B cell line, Ba/F3, and a human leukemia cell line, Jurkat, inhibited G1 to S phase progression through suppression of retinoblastoma protein (Rb) phosphorylation. The dominant gene product, P58, colocalized with mRNA-processing body markers, eukaryotic translation initiation factor 2C and DCP1 decapping-enzyme homolog A, but not with a stress granule maker, T-cell intracellular antigen 1, in the cytoplasm. Taken together with the unique CCCH-type zinc finger motif, the present study suggests that P58 could play an important role in the regulation of cell growth through posttranscriptional modification of cell cycle regulators, at least partially, upstream of Rb. (Mol Cancer Res 2009;7(6):880–9) Introduction Cytogenetic abnormalities contribute not only to cancer initiation but also to tumor progression for many types of malignancies derived from hematopoietic, mesenchymal, and epithelial tissues (1-5). Neither the BCR/ABL fusion protein derived from Philadelphia chromosomes in chronic myeloid leukemia (6, 7) nor BCL-2 overexpression due to the BCL-2 translocation to the immunoglobulin loci in B-cell lymphomas is capable of triggering cell transformation by itself (8, 9). Another genetic mutation is required for full transformation. For example, additional cytogenetic mutations are well documented in chronic myelogenous leukemia blast crisis. Similarly, in the transformation of BCL-2–positive follicular lymphoma into aggressive lymphoma, many cytogenetic abnormalities have been reported (10). Among them, loss of regions in the long arm of chromosome 6 (6q), which is frequently observed not only in hematologic but also in epithelial malignancies (11, 12), has been reported to be associated with poor prognosis (13, 14). These findings suggest the existence of an as yet uncharacterized tumor suppressor gene on 6q21-25. To pave the way for identification of tumor suppressor gene candidates, microarrays such as array based-comparative genomic hybridization, which can visualize gene amplification and/or other defects in cancer, have been used by several groups around the world. Indeed, loss of 6q21-q27 was reported to be frequent in B-cell lymphoma (15, 16). Alternatively, a rare cytogenetic translocation sometimes reveals a novel oncogene or cryptic mutation important for tumorigenesis or leukemogenesis. For example, the tumor suppressor gene HACE1 was first identified from a t(6;15) translocation in a Wilms' tumor sample. Thereafter, HACE1 was shown to be involved in multiple cancers (17, 18). The universal cryptic defect of the α-type platelet-derived growth factor receptor gene (αPDGFR) in chronic eosinophilic leukemia was also first identified from a rare case with t(1;4) (q44;q12) (ref. 19). Thereafter, the genetic change established a new clinical entity defined in the updated WHO classification (20). Recently, we identified a possible tumor suppressor gene at the break points of the t(2;6)(p12;q25) translocation in a transformed follicular lymphoma, designated TFL (21, 22). The break point was located at the putative second intron of ZC3H12D, an orphan gene previously defined by the human genome project (GenBank accession no. NM 207360). The gene presumably encodes a single “Cys-x8-Cys-x5-Cys-x3His” (CCCH)-type zinc finger protein, and was recently reported to be a novel tumor suppressor gene candidate. Its loss of heterozygosity was found in sporadic lung cancer, and a single-nucleotide polymorphism at codon 106 was shown to affect tumor growth (23). However, the TFL gene structure, its gene products, or their physiologic function has not yet been determined. Reports of the exon organization of ZC3H12D transcripts have been frequently rewritten on the web site of National Center for Biotechnology Information (NCBI). To clarify the functional significance of this tumor suppressor gene candidate in cell transformation, we investigated the TFL gene products and their expression profiles and biological function. Received 10/31/08; revised 1/7/09; accepted 2/12/09; publishedOnlineFirst 6/16/09. Grant support: Grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Requests for reprints: Toshimitsu Matsui, Hematology/Oncology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe 650-0017, Japan. Phone: 81-78-382-5885; Fax: 81-78382-5899. E-mail: matsui@med.kobe-u.ac.jp Copyright © 2009 American Association for Cancer Research. doi:10.1158/1541-7786.MCR-08-0511 Mol Cancer Res 2009;7(6). June 2009 880 Published Online First on June 16, 2009 on June 27, 2017. © 2009 American Association for Cancer Research. mcr.aacrjournals.org Downloaded from Published OnlineFirst June 16, 2009; DOI: 10.1158/1541-7786.MCR-08-0511

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@inproceedings{Minagawa2009InhibitionOG, title={Inhibition of G1 to S Phase Progression by a Novel Zinc Finger Protein P58 at P-bodies}, author={Kentaro Minagawa and Yoshio Katayama and Shinichiro Nishikawa and Katsuya Yamamoto and Akiko Sada and Atsuo Okamura and Manabu Shimoyama and Toshimitsu Matsui}, year={2009} }