WHSC1L1, on Human Chromosome 8p11.2, Closely Resembles WHSC1 and Maps to a Duplicated Region Shared with 4p16.3

Stec, Ingrid; Ommen, Gert‐Jan B. van; Dunnen, Johan T. den

doi:10.1006/geno.2001.6581

Cited by 47 publications

(71 citation statements)

References 13 publications

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“…FGFR1 has long been suggested as the driver of this amplicon (Ugolini et al, 1999), but recent studies suggest that this may not be the case (Ray et al, 2004). Many other genes have been suggested as alternate drivers including WHSC1L1 (Stec et al, 2001), TACC1 (Still et al, 1999), LSM1 (Streicher et al, 2006). Our analysis shows that these genes all lie outside the minimal peak.…”

Section: Discussionmentioning

confidence: 59%

High‐resolution genomic and expression analyses of copy number alterations in breast tumors

Haverty¹,

Fridlyand²,

Li³

et al. 2008

Genes Chromosomes & Cancer

139

110

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Analysis of recurrent DNA amplification can lead to the identification of cancer driver genes, but this process is often hampered by the low resolution of existing copy number analysis platforms. Fifty-one breast tumors were profiled for copy number alterations (CNAs) with the high-resolution Affymetrix 500K SNP array. These tumors were also expression-profiled and surveyed for mutations in selected genes commonly mutated in breast cancer (TP53, CDKN2A, ERBB2, KRAS, PIK3CA, PTEN). Combined analysis of common CNAs and mutations revealed putative associations between features. Analysis of both the prevalence and amplitude of CNAs defined regions of recurrent alteration. Compared with previous array comparative genomic hybridization studies, our analysis provided boundaries for frequently altered regions that were approximately one-fourth the size, greatly reducing the number of potential alteration-driving genes. Expression data from matched tumor samples were used to further interrogate the functional relevance of genes located in recurrent amplicons. Although our data support the importance of some known driver genes such as ERBB2, refined amplicon boundaries at other locations, such as 8p11-12 and 11q13.5-q14.2, greatly reduce the number of potential driver genes and indicate alternatives to commonly suggested driver genes in some cases. For example, the previously reported recurrent amplification at 17q23.2 is reduced to a 249 kb minimal region containing the putative driver RPS6KB1 as well as the putative oncogenic microRNA mir-21. High-resolution copy number analysis provides refined insight into many breast cancer amplicons and their relationships to gene expression, point mutations and breast cancer subtype classifications. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

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Section: Discussionmentioning

confidence: 59%

High‐resolution genomic and expression analyses of copy number alterations in breast tumors

Haverty¹,

Fridlyand²,

Li³

et al. 2008

Genes Chromosomes & Cancer

139

110

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“…Similarly, a specific region in human chromosome 8 is reported to be homologous to the crucial WHS region that contains the LETM1 gene (Stec et al, 2001). Because the putative proteins encoded in the rat chromosomal region did not contain an ortholog of human LETM1, we attempted to clone a cDNA sequence that is homologous to the LETM1 gene.…”

Section: Letm2 Is a Mitochondrial Protein That Is Expressed Specificamentioning

confidence: 99%

“…The protein encoded by the cDNA exhibited 32% overall similarity to human LETM1 protein; higher similarity (53.6%) was found for the region between the hydrophobic segment and a putative leucinezipper domain. The gene in human chromosome 8 has already been named LETM2, although the entire protein is still unidentified (Stec et al, 2001). Therefore, we named our cloned gene product rat LETM2 to avoid confusion in the nomenclature.…”

Section: Letm2 Is a Mitochondrial Protein That Is Expressed Specificamentioning

confidence: 99%

Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L

Tamai

Iida

Yokota

et al. 2008

Journal of Cell Science

118

149

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LETM1 is located in the chromosomal region that is deleted in patients suffering Wolf-Hirschhorn syndrome; it encodes a homolog of the yeast protein Mdm38 that is involved in mitochondrial morphology. Here, we describe the LETM1-mediated regulation of the mitochondrial volume and its interaction with the mitochondrial AAA-ATPase BCS1L that is responsible for three different human disorders. LETM1 is a mitochondrial inner-membrane protein with a large domain extruding to the matrix. The LETM1 homolog LETM2 is a mitochondrial protein that is expressed preferentially in testis and sperm. LETM1 downregulation caused mitochondrial swelling and cristae disorganization, but seemed to have little effect on membrane fusion and fission. Formation of the respiratory-chain complex was impaired by LETM1 knockdown. Cells lacking mitochondrial DNA lost active respiratory chains but maintained mitochondrial tubular networks, indicating that mitochondrial swelling caused by LETM1 knockdown is not caused by the disassembly of the respiratory chains. LETM1 was co-precipitated with BCS1L and formation of the LETM1 complex depended on BCS1L levels, suggesting that BCS1L stimulates the assembly of the LETM1 complex. BCS1L knockdown caused disassembly of the respiratory chains as well as LETM1 downregulation and induced distinct changes in mitochondrial morphology.

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“…Previous global genome analysis studies on these cell lines revealed that three cell lines in the panel (SUM-44, SUM-52, and SUM-225) harbor focal copy number increases in the 8p11-12 region (2,3). Furthermore, past and recent studies on primary breast cancer specimens have shown that gene amplification occurs in this region in 10% to 15% of human breast cancers (14,(27)(28)(29)(30)(31). Recent studies from our lab and others have suggested that the heretofore best candidate oncogene from this region (FGFR1) is not the only candidate oncogene in the region and, indeed, may be of marginal significance (32).…”

Section: Introductionmentioning

confidence: 97%

Multiple Interacting Oncogenes on the 8p11-p12 Amplicon in Human Breast Cancer

Yang¹,

Streicher²,

et al. 2006

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The 8p11-p12 genomic region is amplified in 15% of breast cancers and harbors several candidate oncogenes. However, functional evidence for a transforming role for these genes is lacking. We identified 21 genes from this region as potential oncogenes based on statistical association between copy number and expression. We further showed that three of these genes (LSM1, BAG4, and C8orf4) induce transformed phenotypes when overexpressed in MCF-10A cells, and overexpression of these genes in combination influences the growth factor independence phenotype and the ability of the cells to grow under anchorage-independent conditions. Thus, LSM1, BAG4, and C8orf4 are breast cancer oncogenes that can work in combination to influence the transformed phenotype in human mammary epithelial cells. (Cancer Res 2006; 66(24): 11632-43)

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WHSC1L1, on Human Chromosome 8p11.2, Closely Resembles WHSC1 and Maps to a Duplicated Region Shared with 4p16.3

Cited by 47 publications

References 13 publications

High‐resolution genomic and expression analyses of copy number alterations in breast tumors

High‐resolution genomic and expression analyses of copy number alterations in breast tumors

Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L

Multiple Interacting Oncogenes on the 8p11-p12 Amplicon in Human Breast Cancer

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