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Dive into the research topics where Lowell J. Underwood is active.

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Featured researches published by Lowell J. Underwood.


Tumor Biology | 2001

The CA 125 Gene: An Extracellular Superstructure Dominated by Repeat Sequences

Timothy J. O’Brien; John B. Beard; Lowell J. Underwood; Richard A. Dennis; Alessandro D. Santin; Lyndal York

CA 125 has long presented problems to both clinicians and investigators because there was no definitive information on its structure and function. Here, we describe our work on cloning the CA 125 gene with the anticipation that such information will provide the basis for understanding its structure and its physiologic role in both normal and malignant tissues. The CA 125 protein core is composed of a short cytoplasmic tail, a transmembrane domain and an extraordinarily large glycosylated extracellular structure. This structure is dominated by a repeat domain composed of 156 amino acid repeat units which encompass the epitope binding sites. The molecule also includes an amino terminal domain of serine/threonine-rich sequences which would account for most of the O-glycosylation known to be present in CA 125. CA 125 is an unusually large transmembrane glycoprotein. Its release from the surface of the cell is most probably dependent on cytoplasmic phosphorylation followed by proteolytic cleavage. The extracellular domain is characterized by a large number of repeat units (probably 60+) which encompass an interactive disulfide bridged cysteine-loop and the site of OC125 and M11 binding. Sequencing the gene provides us with the ability to initiate the quest to understand the biological function of CA 125.


Tumor Biology | 2002

The CA 125 gene: A newly discovered extension of the glycosylated N-terminal domain doubles the size of this extracellular superstructure

Timothy J. O'Brien; John B. Beard; Lowell J. Underwood; Kazushi Shigemasa

CA 125 is a well-established marker for patients diagnosed with ovarian carcinoma. It is clearly elaborated in serous cystadenocarcinomas and less likely to be expressed in mucinous tumors. It has been 20 years since CA 125 was first recognized and it is only in recent years (the past 2) that some progress has been made toward cloning the gene, providing the basis for an understanding of the functional role of this molecule in embryonic development and neoplastic transformation. It is now clear that CA 125 is a large glycoprotein which is anchored to the epithelium by a transmembrane domain and is released into the extracellular space by enzymatic cleavage. Here, we describe a further major extension to the glycosylated extracellular amino terminal domain of this molecule. These additional data in association with our previous understanding of this molecule will provide the basis for our ability to understand the physiologic function of this molecule in biologic development and pathologic transformation.


Tumor Biology | 2001

Ovarian Tumor Cells Express a Transmembrane Serine Protease: A Potential Candidate for Early Diagnosis and Therapeutic Intervention

Hirotoshi Tanimoto; Lowell J. Underwood; Yinxiang Wang; Kazushi Shigemasa; Tim H. Parmley; Timothy J. O'Brien

Proteases have been implicated in the extracellular modulation required for tumor growth and invasion. In an effort to categorize those proteases contributing to ovarian carcinoma progression, we have utilized redundant primers to conserved amino acid (AA) domains surrounding the catalytic triad of His, Asp and Ser to amplify serine proteases that are differentially expressed in carcinomas. Using this method, we have identified and cloned a serine protease named TADG-15 (tumor-associated differentially expressed gene 15) that is overexpressed in ovarian tumors. TADG-15 is a transmembrane multidomain serine protease which includes ligand binding domains and a serine protease in the extracellular space.


Tumor Biology | 2001

Increased Expression of Protease M in Ovarian Tumors

Hirotoshi Tanimoto; Lowell J. Underwood; Kazushi Shigemasa; Tim H. Parmley; Timothy J. O'Brien

Proteases are known to play important roles in tumor invasion and metastasis. Protease M, which was originally identified by Anisowicz and colleagues in 1996, is a new member of the serine protease family. We also identified the protease M transcript in a differential PCR screen of ovarian tumors and have investigated its expression in 44 ovarian tumors (12 low malignant potential tumors, 32 carcinomas) and 10 normal ovaries using quantitative PCR. The PCR product was labeled with 32P and a phosphoimager was used to determine the relative expression of the protease M gene compared to internal control β-tubulin. mRNA expression levels of protease M were significantly elevated in 9 of 12 low malignant potential tumors and 30 of 32 carcinomas. Northern blot hybridization showed that the 1.7-kb protease M transcript was abundant in carcinoma but not detected in normal ovary. Immunohistochemical staining of normal overy and ovarian tumor tissue sections with antibodies generated to protease M derived peptides corroborated the semi-quantitative PCR and Northern analysis data. Our results suggest that protease M is frequently overexpressed in ovarian tumors and may therefore contribute to the invasive nature or growth capacity of ovarian carcinomas.


Tumor Biology | 1999

The matrix metalloprotease pump-1 (MMP-7, matrilysin) : A candidate marker/target for ovarian cancer detection and treatment

Hirotoshi Tanimoto; Lowell J. Underwood; Kazushi Shigemasa; Tim H. Parmley; Yinxiang Wang; Yan Yan; John Clarke; Timothy J. O'Brien

Matrix metalloproteases are known to play an important role in tumor invasion by mediating degradation of extracellular matrix. In this study, we have investigated the expression of the matrix metalloprotease pump-1 gene (also referred to as MMP-7, Matrilysin) in 44 ovarian tumors (12 low malignant potential tumors, 32 carcinomas) and 10 normal ovaries using quantitative PCR. The PCR product was labelled with 32P and a phosphoimager was used to determine the relative expression of pump-1 compared to an internal control β-tubulin. mRNA expression levels of pump-1 were significantly elevated in 9 of 12 low malignant potential tumors and 26 of 32 carcinomas. Northern blot hybridization showed that the 1.1-kb pump-1 transcript was abundant in carcinoma but seldom expressed in normal adult tissues including normal ovary. Immunohistochemical localization of the pump-1 protein confirms its expression by ovarian tumor cells. Our results suggest that pump-1 is frequently overexpressed in ovarian tumors and may contribute to its invasive nature or growth capacity, therefore pump-1 may serve as a useful marker for early detection of disease and/or a target for therapeutic intervention in downregulation of tumor progression.


Biochimica et Biophysica Acta | 2000

Ovarian tumor cells express a novel multi-domain cell surface serine protease

Lowell J. Underwood; Kazushi Shigemasa; Hirotoshi Tanimoto; John B. Beard; Elizabeth N. Schneider; Yinxiang Wang; Tim H. Parmley; Timothy J. O’Brien

Serine proteases serve many functions in normal biological processes. These functions are often usurped by cancer cells to allow progression of tumors by increasing the growth and metastatic potential of the neoplasia. Here, we have used a polymerase chain reaction (PCR)-based strategy to clone Tumor Associated Differentially-expressed Gene-12 (TADG-12), a new serine protease from ovarian carcinoma. This technique also revealed a variant splicing form of TADG-12 that could lead to a truncated protein product. Semi-quantitative PCR showed that TADG-12 is overexpressed in 41 of 55 ovarian cancer specimens relative to normal expression, and the variant form, TADG-12V is found at increased levels in 8 of 22 carcinomas examined. Northern blot revealed three transcripts, the largest of which is approximately 2.4 kb. An ovarian tumor cDNA library was screened, and the entire cDNA of TADG-12 has been identified. This sequence encodes a putative protein of 454 amino acids which includes a potential transmembrane domain, an LDL receptor-like domain, a scavenger receptor cysteine-rich domain, and a serine protease domain. These features imply that TADG-12 will be at the cell surface, and it may be useful as a molecular target for therapy or a diagnostic marker.


Journal of The Society for Gynecologic Investigation | 2000

Overexpression of testisin, a serine protease expressed by testicular germ cells, in epithelial ovarian tumor cells.

Kazushi Shigemasa; Lowell J. Underwood; John B. Beard; Hirotoshi Tanimoto; Koso Ohama; Tim H. Parmley; Timothy J. O'Brien

Objective: In a continued effort to identify and characterized secreted proteases that are overexpressed in ovarian carcinomas, we discovered the testisin protease as such a candidate. When this discovery was originally made, no data existed in the literature or in the GenBank database that identified such a gene. Our main objective was to determine whether this gene was overexpressed exclusively in ovarian tumor tissues compared with normal ovary and whether it was expressed in any other normal tissues. Methods: mRNA was isolated and cDNA was prepared from 34 ovarian tumors (four adenomas, three low malignant potential tumors, and 37 carcinomas) and seven normal ovaries. The testisin mRNA expression level relative to internal control, β-tubulin, was determined by Northern blot analysis and semiquantitative polymerase chain reaction (PCR). Results: Northern blot hybridization showed that the testisin transcript was abundant in ovarian carcinoma but was not detected in normal ovary. On examination of Northern blots from normal fetal and adult tissues, only adult testis showed abundant transcripts of testisin. Semiquantitative PCR examination showed that the testisin mRNA levels in ovarian tumors of low malignant potential and in ovarian carcinomas were significantly higher than in normal ovaries (P < .01). Testisin mRNA level in ovarian carcinomas was also significantly higher than in ovarian adenomas (P < .05). Testisin overexpression rates in advanced stage (stage 2 or 3) diseases were significantly higher than that in early stage disease (stage 1) in ovarian carcinoma samples (P < .05). Conclusions: The induction of the testisin transcript might contribute to the development, progression, and invasive or metastatic capacity of ovarian carcinomas.


Journal of The Society for Gynecologic Investigation | 1998

Expression of HOXDIO Gene in Normal Endometrium and Endometrial Adenocarcinoma

J. P. Osborne; Changzi Hu; Colleen Hawley; Lowell J. Underwood; Timothy J. O'Brien; Vicki V. Baker

Objective: Hox genes encode DNA transcription regulatory that contain a conserved 61 amino acid protein called the homeodomain. Although best known for their role in cellular differentiation during embryonic development, aberrant expression of these genes has been associated with hematologic and solid neoplasms. The purpose of this study was to determine the relative expression of HOXD10 in huamn endometrial adenocarcionmas. Methods: mRNA was isolated from 7 normal endometrial specimens and 28 endometrial adenocarcinoma specimens. cDNA was synthesized using randon hexamer primers. The expression of HOXD10 relative to βtubulin (internal control) was assessed by densitometric comparison of co-amplified Phosphorus-32 (32P) labeled gene products separated by agarose gel electrophoesis. Direct sequencing of purified HOXD10 polymerase chain reaction product was also performed. Results: The sequence of the purified HOXD10 product corresponds to the known DNA sequence reported in the National Institutes of Health Gene Bank. mRNA expression of HOXD10 relative to β-tubulin is significantly lower in endometrial carcinomas than in normal endometrium. Furthermore, the ratio of HOXD10 to β-tubulin expression varies inversely with the histologic grade of the tumor (P = .0009). Conclusion: Cancer is a multistep proces involving aberrant expression of genes that regulate cell growth and differentiation. Human HOXD10 gene expression is altered in endometrial carcinoma and varies with the histologic grade of differentiation. This observation supports the theory that homeobox genes play a role in oncogenesis.


Cancer Research | 1999

Cloning of Tumor-associated Differentially Expressed Gene-14, a Novel Serine Protease Overexpressed by Ovarian Carcinoma

Lowell J. Underwood; Hirotoshi Tanimoto; Yinxiang Wang; Kazushi Shigemasa; Tim H. Parmley; Timothy J. O'Brien


International Journal of Gynecological Cancer | 2001

Expression of the protease inhibitor antileukoprotease and the serine protease stratum corneum chymotryptic enzyme (SCCE) is coordinated in ovarian tumors

Kazushi Shigemasa; Hirotoshi Tanimoto; Lowell J. Underwood; Tim H. Parmley; K. Arihiro; Koso Ohama; Timothy J. O'Brien

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Timothy J. O'Brien

University of Arkansas for Medical Sciences

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Hirotoshi Tanimoto

University of Arkansas for Medical Sciences

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John B. Beard

University of Arkansas for Medical Sciences

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Tim H. Parmley

University of Arkansas for Medical Sciences

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Timothy J. O’Brien

University of Arkansas for Medical Sciences

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Yinxiang Wang

University of Arkansas for Medical Sciences

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Lyndal York

University of Arkansas for Medical Sciences

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