WWOX, the common chromosomal fragile site, FRA16D, cancer gene
WWOX, the common chromosomal fragile site, FRA16D, cancer gene
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DOI：
10.1159/000072844
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发表时间：
2003-01-01
影响因子：
1.7
通讯作者：
Aldaz, CM
中科院分区：
文献类型：
--
作者：
Ludes-Meyers, JH;Bednarek, AK;Aldaz, CM
总体染色体重排和非整倍性是在癌症起始和进展期间，特别是在人类实体瘤癌变过程中发生的最常见的体细胞基因组异常。由于总重排（例如缺失）而导致的大染色体区域的丢失。单体性、不平衡易位和有丝分裂重组）传统上与受遗传物质损失影响的区域内肿瘤抑制基因的存在有关。染色体16的长臂被鉴定为经常与多发性肿瘤的结构异常相关，这使我们将注意力集中在该区域的详细遗传解剖上，从而克隆了推定的肿瘤抑制基因WWOX（含氧化还原酶的WW结构域）。有趣的是，WWOX基因与常见的染色体脆性位点16 D（FRA 16 D）位于同一区域。WWOX基因编码的蛋白质包含两个WW结构域，参与蛋白质-蛋白质相互作用，和一个短链脱氢酶（SDR）结构域，可能参与性类固醇代谢。我们已经确定了WWOX WW结构域配体作为PPXY基序，证实了该结构域的生物化学活性。WWOX通常驻留在高尔基体，我们将证明高尔基体本地化需要一个完整的SDR。肿瘤发生过程中WWOX基因的失活可能通过纯合缺失和可能的突变发生，然而，即使当一个等位基因仍然完整时，也观察到WWOX mRNA的异常剪接形式。异常剪接的mRNA具有编码SDR的外显子的缺失，并且这些WWOX蛋白同种型显示异常的细胞内定位至细胞核，可能作为全长WWOX的显性负性抑制剂起作用。因此，WWOX的异常转录物的产生可能代表了一种新的机制，以功能性地抑制WWOX，而不改变其余等位基因的基因组。本文就FRA 16 D靶基因WWOX的克隆和鉴定作一综述。此外，我们将讨论WWOX可能的生化功能，并提出证据表明，异位WWOX表达抑制肿瘤生长。版权所有（C）2002 S. Karger AG，巴塞尔。
Gross chromosomal rearrangements and aneuploidy are among the most common somatic genomic abnormalities that occur during cancer initiation and progression, in particular in human solid tumor carcinogenesis. The loss of large chromosomal regions as consequence of gross rearrangements (e.g. deletions.. monosomies, unbalanced translocations and mitotic recombination) have been traditionally associated with the existence of tumor suppressor genes within the areas affected by the loss of genetic material. The long arm of chromosome 16 was identified as being frequently associated with structural abnormalities in multiple neoplasias, that led us to focus attention on the detailed genetic dissection of this region resulting in the cloning of the putative tumor suppressor gene, WWOX (WW domain containing Oxidoreductase). Interestingly, the WWOX gene resides in the very same region as that of the common chromosomal fragile site 16D (FRA16D). The WWOX gene encodes a protein that contains two WW domains, involved in protein-protein interactions, and a short chain dehydrogenase (SDR) domain, possibly involved in sex-steroid metabolism. We have identified the WWOX WW domain ligand as the PPXY motif confirming the biochemical activity of this domain. WWOX normally resides in the Golgi and we will demonstrate that Golgi localization requires an intact SDR. Inactivation of the WWOX gene during tumorigenesis can occur by homozygous deletions and possibly mutation, however, aberrantly spliced forms of WWOX mRNA have been observed even when one allele is still intact. The aberrantly spliced mRNAs have deletions of the exons that encode the SDR and these WWOX protein isoforms display abnormal intracellular localization to the nucleus possibly functioning as dominant negative inhibitors of full length WWOX. Thus, generation of aberrant transcripts of WWOX may represent a novel mechanism to functionally inactivate WWOX without genomic alteration of the remaining allele. In this article we will review the cloning and identification of WWOX as the target of FRA16D. In addition, we will discuss the possible biochemical functions of WWOX and present evidence that ectopic WWOX expression inhibits tumor growth. Copyright (C) 2002 S. Karger AG, Basel.