Abstract
doc-1 is a putative tumor suppressor gene isolated and identified from the hamster oral cancer model. Here, we report the molecular cloning and the functional characterization of the human ortholog of the hamster doc-1 gene. Human doc-1 cDNA is 1.6 kilobase pairs in length and encodes for a 115-amino acid polypeptide (12.4 kDa, pI 9. 53). Sequence analysis showed 98% identity between human and hamster doc-1 protein sequences. DOC-1 is expressed in all normal human tissues examined. In oral keratinocytes, expression of DOC-1 is restricted to normal oral keratinocytes. By immunostaining of normal human mucosa, DOC-1 is detected in both the cytoplasm and nuclei of basal oral keratinocytes; while in suprabasilar cells, it is primarily found in the nuclei. Human oral cancers in vivo did not exhibit immunostaining for DOC-1. Like murine DOC-1, human DOC-1 associates with DNA polymerase alpha/primase and mediates the phosphorylation of the large p180 catalytic subunit, suggesting it may be a potential regulator of DNA replication in the S phase of the cell cycle. Using a human doc-1 cosmid as a probe, human doc-1 is mapped to chromosome 12q24. We identified four exons in the entire human doc-1 gene and determined the intron-exon boundaries. By polymerase chain reaction and direct sequencing, we examined premalignant oral lesion and oral cancer cell lines and found no intragenic mutations.
Highlights
Squamous cell carcinoma (SCC)1 of the oral cavity is newly diagnosed in 38,000 Americans each year and in 350,000 people worldwide [1, 2]
Immunohistochemical Staining for DOC-1 in Normal and Tumor Oral Epithelia—Three normal oral mucosal tissues and five primary oral squamous cell carcinoma were subjected to DOC-1 immunohistochemical study
DNAs isolated from the premalignant and malignant human oral keratinocyte cell lines were polymerase chain reaction-amplified, and the polymerase chain reaction products were directly sequenced to examine for any intragenic mutations
Summary
6704 –6709, 1998 Printed in U.S.A. Cloning, Mapping, Expression, Function, and Mutation Analyses of the Human Ortholog of the Hamster Putative Tumor Suppressor Gene doc-1*. Doc-1 is a putative tumor suppressor gene identified and isolated from the carcinogen-induced hamster oral cancer model [8]. We have recently cloned the full-length mouse doc-1 cDNA (GenBankTM number AF011644); its DNA sequence in the open reading frame is 94% identical to that of the hamster. The highly conserved nature of the rodent doc-1 genes prompted us to clone and examine the role of doc-1 in human oral and other cancers. This paper describes the cDNA and genomic DNA cloning of the human doc-1 gene, its chromosome localization, and its expression in normal and transformed human tissues. The potential interaction of human DOC-1 with DNA-PP was examined
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