TOM1Genes Map to Human Chromosome 22q13.1 and Mouse Chromosome 8C1 and Encode Proteins Similar to the Endosomal Proteins HGS and STAM

doi:10.1006/geno.1998.5739

Genomics

Volume 57, Issue 3, 1 May 1999, Pages 380-388

https://doi.org/10.1006/geno.1998.5739 Get rights and content

Abstract

The aviantom1(target of myb 1) gene has been previously characterized from v-myb-transformed cells. We report here cloning of the human and mousetom1orthologs. Both genes are expressed ubiquitously, with the highest levels in skeletal muscle, brain, and intestines, as assessed by Northern blot and mRNAin situhybridization. The N-terminal domain of the TOM1 protein shares similarity with HGS (hepatocyte growth factor-regulated tyrosine kinase substrate) and STAM (signal-transducing adaptor molecule), which are associated with vesicular trafficking at the endosome. A putative coiled-coil domain was also detected in the central part of the TOM1 protein. This domain structure suggests thatTOM1is another member of a family of genes implicated in the trafficking regulation of growth-factor-receptor complexes that are destined for degradation in the lysosome. We also show that a human paralog ofTOM1(TOM1-like gene 1) exists. Furthermore, we provide a transcription map over a 190-kb contig of theTOM1region. This map includes its distal neighborsHMOX1andMCM5and two proximal novel genes, one of which is a HMG-box-containing gene (HMG2L1), and the other of unknown function. Using a genomic PAC clone, we demonstrate that the mouseTom1andHmox1genes are part of an as yet undescribed syntenic group between mouse chromosome 8C1 and human chromosome 22q13.1.

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We identified the cellular HMG2L1 protein as a cellular interactor of the SB transposase (Figure 3). HMG2L1 is an HMG-box DNA-binding domain-containing protein38 that shares structural similarity with the LEF-1, Sox-4 and SRY proteins. These proteins bind to DNA in a sequence-specific fashion through minor groove contacts, and alter DNA conformation upon binding.32
The Sleeping Beauty (SB) transposable element shows efficient transposition in human cells, and provides long-term transgene expression in preclinical animal models. Random chromosomal insertion of SB vectors represents a safety issue in human gene therapeutic applications, due to potential genotoxic effects associated with transposon integration. We investigated the transcriptional activities of SB in order to assess its potential to alter host gene expression upon integration. The untranslated regions (UTRs) of the transposon direct convergent, inward-directed transcription. Transcription from the 5′-UTR of SB is upregulated by the host-encoded factor high-mobility group 2-like 1 (HMG2L1), and requires a 65–base pair (bp) region not present in commonly used SB vectors. The SB transposase antagonizes the effect of HMG2L1, suggesting that natural transposase expression is under a negative feedback regulation. SB transposon vectors lacking the 65-bp region associated with HMG2L1-dependent upregulation exhibit benign transcriptional activities, at a level up to 100-times lower than that of the murine leukemia virus (MLV) long terminal repeat (LTR). Incorporation of chicken β-globin HS4 insulator sequences in SB-based vectors reduces the transactivation of model promoters by transposon-borne enhancers, and thus may lower the risk of transcriptional activation of host genes situated close to a transposon insertion site.
TOM1L1 is a Lyn substrate involved in FcεRI signaling in mast cells
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TOM1L1 is one of the clones that we identified in the phosphorylation screen with Lyn. The gene of TOM1L1 was identified as a human paralog of the avian TOM1 (39). However, the function of this protein is still not very clear.
Protein-tyrosine kinase Lyn and Syk are critical for antigen-receptor-induced signal transduction in mast cells. To identify novel Lyn/Syk substrates, we screened an RBL-2H3 bacterial expression library for proteins that were tyrosine phosphorylated with baculoviral expressed Lyn or Syk. Five clones as potential Lyn substrates and eight clones as Syk substrates were identified including known substrates such as SLP-76, LAT, and α-tubulin. A potential substrate of Lyn identified was the molecule TOM1L1, which has several domains thought to be important for membrane trafficking and protein-protein interactions. Because the function of TOM1L1 is unclear, the rat TOM1L1 full-length cDNA was isolated and used to express the protein in COS-1 and RBL-2H3 mast cells. In COS-1 cells, the co-transfection of TOM1L1 and Lyn, but not Syk, resulted in the tyrosine phosphorylation of TOM1L1. In RBL-2H3 mast cells, the overexpressed TOM1L1 was strongly tyrosine phosphorylated in non-stimulated cells, and this phosphorylation was enhanced by FcϵRI aggregation. By subcellular fractionation, wild-type TOM1L1 was mainly in the cytoplasm with a small fraction constitutively associated with the membrane; this association was markedly reduced in deletion mutants lacking several of the protein interaction domains. The overexpression of TOM1L1 enhanced antigen-induced tumor necrosis factor (TNF) α generation and release. Both protein interaction domains (VHS and the coiled-coil domains) were required for the increased TNFα release, but not the increased TNFα generation. These results suggest that TOM1L1 is a novel protein involved in the FcϵRI signal transduction for the generation of cytokines.
Cloning and characterization of cellular senescence-associated genes in human fibroblasts by suppression subtractive hybridization
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Cellular senescence marks the end of the proliferative life span of normal cells in tissue culture and occurs after cells have undergone a certain number of population doublings (PDLs). It is accompanied by alterations in the pattern of gene expression. A specific human embryonic lung diploid fibroblast cell line, 2BS, has been studied as a model of senescence in our laboratory. Here, we report a set of cellular senescence-associated genes identified from suppression subtractive cDNA libraries from senescent and young 2BS cells. They include three novel genes and six previously identified genes of unknown function. The genes whose functions are known belong to various functional pathways that have been reported to change with the onset of senescence. These include three pre-mRNA splicing factors with reduced expression in senescent cells, indicating that the regulation of mRNA splicing is altered during cell senescence. In addition, the expression of the gene TOM1 (target of Myb 1), which has not previously been associated with cellular senescence, is shown to increase in senescent cells, and we demonstrate that the expression of antisense TOM1 gene in 2BS cells can delay the progress of senescence.
Endofin Recruits TOM1 to Endosomes
2004, Journal of Biological Chemistry
Citation Excerpt :
Endofin Interacts Specifically with TOM1 but Not TOM1-L1 or TOM1-L2—A search of the data base reveals that TOM1 is a member of a family of three closely related proteins. The sequences of the two other members, namely TOM1-like 1 (TOM1-L1) (37, 39) and TOM1-like 2 (TOM1-L2) (accession number AF467441), have been reported. Alignment of the three sequences suggests a similar structural organization for the proteins, including a putative amino-terminal VHS and a central GAT domain (Fig. 4A).
Endofin is an endosomal protein implicated in regulating membrane trafficking. It is characterized by the presence of a phosphatidylinositol 3-phosphate-binding FYVE domain positioned in the middle of the molecule. To determine its potential effectors or binding partners, we used the carboxyl-terminal half of endofin as bait to screen a human brain cDNA library in a yeast two-hybrid system. Three clones that encode TOM1 were recovered. TOM1 is a protein closely related to the VHS (VPS-27, Hrs, and STAM) domain-containing GGA family. Although the function of the GGAs in mediating Golgi to lysosomal trafficking is well established, the subcellular localization and function of TOM1 remain unknown. Glutathione S-transferase pull-down assays as well as co-immunoprecipitation experiments confirmed that the carboxyl-terminal half of endofin binds specifically to the carboxyl-terminal region of TOM1. Neither SARA nor Hrs, two other FYVE domain proteins, interact with this region of TOM1. Moreover, endofin does not interact with the analogous region of two other members of the TOM1 protein family, namely, TOM1-like 1 (TOM1-L1) or TOM1-like 2 (TOM1-L2). The carboxyl-terminal region of TOM1 was used as immunogen to generate TOM1-specific antibody. This antibody can distinguish TOM1 from the other family members as well as coimmunoprecipitate endogenous endofin. It also revealed the primarily cytosolic distribution of TOM1 in a variety of cell types by immunofluorescence analyses. In addition, sucrose density gradient analysis showed that both TOM1 and endofin can be detected in cellular compartments marked by the early endosomal marker EEA1. A marked recruitment of TOM1 to endosomes was observed in cells overexpressing endofin or its carboxyl-terminal fragment, indicating TOM1 to be an effector for endofin and suggesting a possible role for TOM1 in endosomal trafficking.
The origin recognition complex marks a replication origin in the human TOP1 gene promoter
2002, Journal of Biological Chemistry
Citation Excerpt :
Two of the sequences were detected at high copy numbers in independent immunoprecipitates of cross-linked chromatin. One of the sequences corresponded to a region close to the geneTOM1 on human chromosome 22q13.1 (59). The cloned sequence revealed a higher than average G+C content (51%), with consecutive CpG dinucleotides and is, therefore, related to mapped ORC binding regions at active genes.
The locations of the origin recognition complex (ORC) in mammalian genomes have been elusive. We have therefore analyzed the DNA sequences associated with human ORC via in vivo cross-linking and chromatin immunoprecipitation. Antibodies specific for hOrc2 protein precipitate chromatin fragments that also contain other ORC proteins, suggesting that the proteins form multisubunit complexes on chromatin in vivo. A binding region for ORC was identified at the CpG island upstream of the humanTOP1 gene. Nascent strand abundance assays show that the ORC binding region coincides with an origin of bidirectional replication. The TOP1 gene includes two well characterized matrix attachment regions. The matrix attachment region elements analyzed contain no ORC and constitute no sites for replication initiation. In initial attempts to use the chromatin immunoprecipitation technique for the identification of additional ORC sites in the human genome, we isolated a sequence close to another actively transcribed gene (TOM1) and an alphoid satellite sequence that underlies centromeric heterochromatin. Nascent strand abundance assays gave no indication that the heterochromatin sequence serves as a replication initiation site, suggesting that an ORC on this site may perform functions other than replication initiation.
Comments on nomenclature of TOM genes/proteins and characterization of ψ4Tom20, a novel processed pseudogene of the human Tom20 gene
2000, Genomics

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^☆: Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under Accession Nos. AJ006973 (Homo sapiensmRNA for TOM1 protein); AJ006972 (Mus musculusmRNA for Tom1 protein); AC005290 (M. musculusChromosome 8 PAC Clone 411O19); AJ010069 (Human high mobility group box containing gene HMG2L1); AJ010070 (Human partial transcript encompassing THC211630-gene); and AJ010071 (HumanTOM1like gene 1, TOM1L1).

¹: To whom correspondence should be addressed. Telephone: +46-8-517 73922 or 72229. Fax: +46-8-517 73909. E-mail:Jan.Dumanski@ cmm.ki.se.

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Regular ArticleTOM1Genes Map to Human Chromosome 22q13.1 and Mouse Chromosome 8C1 and Encode Proteins Similar to the Endosomal Proteins HGS and STAM☆

Abstract

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Genomics

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J. Biol. Chem.

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Hrs-2 is an ATPase implicated in calcium-regulated secretion

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Tom-1, a novel v-myb target gene expressed in amv- and e26-transformed myelomonocytic cells

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CDC46/MCM5, a yeast protein whose subcellular localization is cell cycle-regulated, is involved in DNA replication at autonomously replicating sequences

Proc. Natl. Acad. Sci. USA

Cloning and sequence analysis of a cDNA encoding rat preprocholecystokinin

Proc. Natl. Acad. Sci. USA

Regular Article
TOM1Genes Map to Human Chromosome 22q13.1 and Mouse Chromosome 8C1 and Encode Proteins Similar to the Endosomal Proteins HGS and STAM☆