Inhibins/activins as diagnostic markers for ovarian cancer

Robertson, David; Stephenson, T; Pruysers, Enid; Burger, Henry G.; McCloud, Peter M; Tsigos, Anna; Groome, Nigel P.; Mamers, Pamela; McNeilage, Jane; Jobling, Tom; Healy, David

doi:10.1016/s0303-7207(02)00060-6

Cited by 56 publications

(33 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Inhibin A ELISA-An inhibin A ELISA (Diagnostic Systems Laboratories, Webster, Texas) was used as described (31), employing kit reagents provided by Oxford Bio-Innovation Ltd. (Upper Heyford, UK). The ELISA utilized the ␤ A -subunit antibody (E4) as capture antibody and ␣ subunit antibody (R1) as label.…”

Section: Methodsmentioning

confidence: 99%

A Common Biosynthetic Pathway Governs the Dimerization and Secretion of Inhibin and Related Transforming Growth Factor β (TGFβ) Ligands

Walton

Makanji

Wilce

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

The assembly and secretion of transforming growth factor ␤ superfamily ligands is dependent upon non-covalent interactions between their pro-and mature domains. Despite the importance of this interaction, little is known regarding the underlying regulatory mechanisms. In this study, the binding interface between the pro-and mature domains of the inhibin ␣-subunit was characterized using in vitro mutagenesis. Three hydrophobic residues near the N terminus of the prodomain (Leu 30 , Phe 37 , Leu 41 ) were identified that, when mutated to alanine, disrupted heterodimer assembly and secretion. It is postulated that these residues mediate dimerization by interacting non-covalently with hydrophobic residues (Phe 271 , Ile 280 , Pro 283 , Leu 338 , and Val 340 ) on the outer convex surface of the mature ␣-subunit. Homology modeling indicated that these mature residues are located at the interface between two ␤-sheets of the ␣-subunit and that their side chains form a hydrophobic packing core. Mutation of these residues likely disturbs the conformation of this region, thereby disrupting noncovalent interactions with the prodomain. A similar hydrophobic interface was identified spanning the pro-and mature domains of the inhibin ␤ A -subunit. Mutation of key residues, including Ile 62 , Leu 66 , Phe 329 , and Pro 341 , across this interface was disruptive for the production of both inhibin A and activin A. In addition, mutation of Ile 62 and Leu 66 in the ␤ A -propeptide reduced its ability to bind, or inhibit the activity of, activin A. Conservation of the identified hydrophobic motifs in the proand mature domains of other transforming growth factor ␤ superfamily ligands suggests that we have identified a common biosynthetic pathway governing dimer assembly.Inhibin A and B, members of the transforming growth factor ␤ (TGF␤) 3 superfamily, negatively regulate the production and secretion of follicle-stimulating hormone from the anterior pituitary (1, 2), control ovarian follicle development and steroidogenesis (3), and act as tumor suppressors in the gonads (4). Outside the hypothalamic pituitary gonadal axis, inhibins contribute to the endocrine regulation of bone metabolism (5) and play critical roles in adrenal gland growth and function (6, 7). It is recognized that inhibins regulate these processes by inhibiting the stimulatory actions of the structurally related proteins, activins (8). Inhibins are heterodimers of an 18-kDa ␣-subunit disulfide linked to one of two 13-kDa ␤-subunits (␤ A and ␤ B ), resulting in inhibin A or inhibin B, respectively. Activins are composed of two ␤-subunits: ␤ A -␤ A (activin A), ␤ A -␤ B (activin AB), and ␤ B -␤ B (activin B). Inhibin antagonism of activin-related ligands is dependent upon interactions with betaglycan, a cell surface proteoglycan that also acts as a TGF␤2 co-receptor (9). Betaglycan binds inhibin A directly and promotes the formation of a stable high affinity complex involving activin type II receptors (10). Sequestration of type II receptors in this way prevents their ...

show abstract

Section: Methodsmentioning

confidence: 99%

A Common Biosynthetic Pathway Governs the Dimerization and Secretion of Inhibin and Related Transforming Growth Factor β (TGFβ) Ligands

Walton

Makanji

Wilce

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Available data show that inhibin assays that detect all inhibin forms, i.e. assays that detect the ␣ subunit both as the free form and as an ␣␤ subunit dimer provide the highest sensitivity/specificity characteristics as an ovarian cancer diagnostic test (15). Kallikrein…”

Section: Ovx1mentioning

confidence: 99%

Progress and Challenges in Screening for Early Detection of Ovarian Cancer

Jacobs

Menon

2004

Molecular & Cellular Proteomics

421

312

View full text Add to dashboard Cite

Ovarian cancer is characterize by few early symptoms, presentation at an advanced stage, and poor survival. As a result, it is the most frequent cause of death from gynecological cancer. During the last decade, a research effort has been directed toward improving outcomes for ovarian cancer by screening for preclinical, early stage disease using both imaging techniques and serum markers. Numerous biomarkers have shown potential in samples from clinically diagnosed ovarian cancer patients, but few have been thoroughly assessed in preclinical disease and screening. The most thoroughly investigated biomarker in ovarian cancer screening is CA125. Prospective studies have demonstrated that both CA125 and transvaginal ultrasound can detect a significant proportion of preclinical ovarian cancers, and refinements in interpretation of results have improved sensitivity and reduced the false-positive rate of screening. There is preliminary evidence that screening can improve survival, but the impact of screening on mortality from ovarian cancer is still unclear. Prospective studies of screening are in progress in both the general population and high-risk population, including the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKC-TOCS), a randomized trial involving 200,000 postmenopausal women designed to document the impact of screening on mortality. Recent advances in technology for the study of the serum proteome offer exciting opportunities for the identification of novel biomarkers or patterns of markers that will have greater sensitivity and lead time for preclinical disease than CA125. Considerable interest and controversy has been generated by initial results utilizing surface-enhanced laser desorption/ionization (SELDI) in ovarian cancer. There are challenging issues related to the design of studies to evaluate SELDI and other proteomic technology, as well as the reproducibility, sensitivity, and specificity of this new technology. Large serum banks such as that assembled in UKCTOCS, which contain preclinical samples from patients who later developed ovarian cancer and other disorders, provide a unique resource for carefully designed studies of proteomic technology. There is a sound basis for optimism that further developments in serum proteomic analysis will provide powerful methods for screening in ovarian cancer and many other diseases.

show abstract

“…Application of the total inhibin assay (Lappohn et al 1989, Healy et al 1993, Robertson et al 1999a) and in particular the more recently developed total inhibin ELISA (Robertson et al 2002b) to serum from postmenopausal women with ovarian cancer showed that these assays were suitable for detecting GCT and a high proportion of mucinous carcinomas, but were less effective in detecting other epithelial carcinomas (Table 4). Additional studies determining serum inhibin levels in postmenopausal women with benign tumours (Robertson et al 2002a) showed a range of responses -10% for benign cysts, 54% for mucinous cystadenomas and 100% for thecomas.…”

Section: Serum Inhibin As a Marker Of Gct And Mucinous Tumoursmentioning

confidence: 99%

Inhibin/activin and ovarian cancer.

Robertson¹,

Burger²,

Fuller³

2004

Endocr Relat Cancer

View full text Add to dashboard Cite

Inhibin and activin are members of the transforming growth factor beta (TGFb) family of cytokines produced by the gonads, with a recognised role in regulating pituitary FSH secretion. Inhibin consists of two homologous subunits, a and either bA or bB (inhibin A and B). Activins are hetero-or homodimers of the b-subunits. Inhibin and free a subunit are known products of two ovarian tumours (granulosa cell tumours and mucinous carcinomas). This observation has provided the basis for the development of a serum diagnostic test to monitor the occurrence and treatment of these cancers. Transgenic mice with an inhibin a subunit gene deletion develop stromal/granulosa cell tumours suggesting that the a subunit is a tumour suppressor gene. The role of inhibin and activin is reviewed in ovarian cancer both as a measure of proven clinical utility in diagnosis and management and also as a factor in the pathogenesis of these tumours. In order to place these findings into perspective the biology of inhibin/activin and of other members of the TGFb superfamily is also discussed.

show abstract

Inhibins/activins as diagnostic markers for ovarian cancer

Cited by 56 publications

References 38 publications

A Common Biosynthetic Pathway Governs the Dimerization and Secretion of Inhibin and Related Transforming Growth Factor β (TGFβ) Ligands

A Common Biosynthetic Pathway Governs the Dimerization and Secretion of Inhibin and Related Transforming Growth Factor β (TGFβ) Ligands

Progress and Challenges in Screening for Early Detection of Ovarian Cancer

Inhibin/activin and ovarian cancer.

Contact Info

Product

Resources

About