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Mutational analysis of activin/transforming growth factor-beta type I and type II receptor kinases in human pituitary
F H D'Abronzo1, B Swearingen, A Klibanski
1Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
Abstract:
Genetic mutation or loss of activin/transforming growth factor-beta (TGFbeta) receptor function has been shown in human lymphoid, breast, and colorectal tumors as well as Hep2B and Mv1Lu cell lines. Although activin stimulates FSHbeta biosynthesis and secretion, a large percentage of human gonadotroph tumors have previously been demonstrated to be nonresponsive to characterized activin effects. This phenotype may be indicative of loss of functional cell surface receptors and/or intracellular signaling mediators of activin responses. Several studies examining the structure/function of type I and II receptors specific for ligands in the TGFbeta superfamily have delineated the critical regions for receptor intracellular kinase function. In the case of TGFbeta, inactivating mutations in these regions have been shown to render these receptors kinase deficient by a dominant negative phenotype and result in resistance to growth arrest. We therefore hypothesized that activin/TGFbeta cell surface receptors may act as tumor suppressors in human pituitary tumors, and that inactivating genetic mutations in the intracellular kinase region of this gene family may release pituicytes from normal growth suppression by activin through a similar mechanism. We used single stranded conformational polymorphism analysis to examine 2 intracellular regions required for type I receptor signaling by human Alk1-5 type I receptors as well as the entire coding region of 2 activin type II receptors and the TGFbeta type II receptor in 64 human pituitary tumors. A novel polymorphism was found in 45% of tumors at codon P117 of the ActRIIA gene and was used as a positive control for single stranded conformational polymorphism. One patient with a gonadotroph tumor had a confirmed A482V germline mutation in the Alk1 gene within kinase subdomains X-XI. No other mutations were detected in any tumor studied. These data suggest that somatic mutations within these intracellular kinase regions of type I/type II receptors are rare in human pituitary tumors.
Insights
Genetic mutations in activin/transforming growth factor-beta (TGFbeta) receptors, which may act as tumor suppressors, are rare in human pituitary tumors. Researchers investigated these receptors in 64 pituitary tumors, finding limited evidence of inactivating mutations. This suggests other mechanisms may be involved in pituitary tumor development.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Loss of activin/transforming growth factor-beta (TGFbeta) receptor function is implicated in various human tumors.
- Activin normally stimulates FSHbeta, but gonadotroph tumors often lack responsiveness, suggesting receptor dysfunction.
- TGFbeta superfamily receptors have critical intracellular kinase regions; mutations here can lead to dominant-negative effects and resistance to growth arrest.
Purpose of the Study:
- To investigate the hypothesis that activin/TGFbeta receptors act as tumor suppressors in human pituitary tumors.
- To determine if inactivating mutations in the intracellular kinase regions of these receptors contribute to pituitary tumor development by releasing cells from growth suppression.
Main Methods:
- Single-stranded conformational polymorphism (SSCP) analysis was used to examine specific intracellular regions of Alk1-5 type I receptors, and the coding regions of two activin type II receptors and the TGFbeta type II receptor.
- The study analyzed DNA from 64 human pituitary tumors.
- A novel polymorphism in the ActRIIA gene was identified in 45% of tumors, serving as a positive control for SSCP.
Main Results:
- A novel polymorphism was detected in 45% of pituitary tumors within the ActRIIA gene.
- One patient with a gonadotroph tumor exhibited a confirmed A482V germline mutation in the Alk1 gene.
- No other somatic mutations were found in the examined intracellular kinase regions of type I/II receptors across the 64 pituitary tumors.
Conclusions:
- Somatic mutations within the intracellular kinase regions of type I and type II activin/TGFbeta receptors appear to be infrequent in human pituitary tumors.
- The findings suggest that other mechanisms, beyond inactivating mutations in these specific receptor regions, likely contribute to the development of pituitary tumors.