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Tumor-specific expression and alternate splicing of messenger ribonucleic acid encoding activin/transforming growth
J M Alexander1, H A Bikkal, N T Zervas
1Department of Medicine, Massachusetts General Hospital, Boston 02114, USA.
Abstract:
Activin, a member of the transforming growth factor-beta (TGF beta) cytokine family, acts as a pituitary cell mitogen via a novel family of receptor-linked serine/threonine (Ser/Thr) kinases. Pituitary tumors synthesize activin subunits, and the autocrine action of these growth factors may modulate tumor proliferation. We, therefore, investigated the expression of activin/TGF beta type I receptor messenger ribonucleic acids (mRNAs), designated ALK1 through ALK5 (ALK = activin receptor-like kinase), and type II receptor mRNAs using RT-PCR in 34 human pituitary adenomas of all phenotypes and normal pituitary tissue. ALK2 and ALK5, specific mediators of activin and TGF beta signals, respectively, were found to be expressed only in tumor and not in normal pituitary cells, and ALK2 expression was found only in tumors of a mammosomatotroph cell lineage. ALK1, ALK3, and ALK4 mRNAs were found in both normal and neoplastic pituitary cells. The alternatively spliced cytoplasmic domain of ALK4 consists of 11 kinase subdomains, that are critical for modulating receptor function and intracellular signaling. Truncated forms of the ALK4 cytoplasmic domain lacking these subdomains may attenuate activin signal transduction and affect both tumor phenotype and proliferation via the formation of inactive type I/type II complexes. Three truncated ALK4 receptor mRNAs generated by alternate splicing of the cytoplasmic Ser/Thr kinase domain were found to be tumor specific. One of these truncated receptor mRNAs, ALK4-5, is a novel splice variant that has not been previously described. Expression of the ActRII and T beta RII type II receptor mRNAs, which specifically bind activin and TGF beta, respectively, was highly prevalent among all tumor subtypes and normal pituitary tissue. However, ActRIIB, an activin-specific type II receptor that displays a 3- to 4-fold higher affinity for ligand than ActRII, was expressed in 94% of tumors, but was not prevalent in normal tissue. These data are the first to demonstrate tumor-specific expression of Ser/Thr kinase receptors mRNAs and their splice variants in human pituitary adenomas.
Insights
Pituitary tumors show unique expression of activin/transforming growth factor-beta (TGF beta) type I and type II receptors, including novel splice variants. These findings highlight specific receptor signaling pathways involved in pituitary adenoma development and proliferation.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Activin, a member of the transforming growth factor-beta (TGF beta) cytokine family, acts as a pituitary cell mitogen.
- Pituitary tumors synthesize activin subunits, potentially modulating tumor proliferation through autocrine signaling.
Purpose of the Study:
- To investigate the expression of activin/TGF beta type I receptor (activin receptor-like kinase - ALK) and type II receptor messenger ribonucleic acids (mRNAs) in human pituitary adenomas.
- To identify tumor-specific receptor expression and splice variants that may contribute to pituitary tumor development.
Main Methods:
- Reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze mRNA expression.
- 34 human pituitary adenomas and normal pituitary tissue samples were examined.
Main Results:
- Specific type I receptors, ALK2 and ALK5, were expressed only in tumors, with ALK2 found in mammosomatotroph lineage tumors.
- Tumor-specific truncated ALK4 receptor mRNAs, including a novel variant ALK4-5, were identified.
- The activin type II receptor, ActRIIB, showed higher prevalence in tumors compared to normal tissue.
Conclusions:
- This study demonstrates tumor-specific expression of serine/threonine kinase receptors and their splice variants in human pituitary adenomas.
- These findings suggest a role for specific receptor signaling pathways and novel splice variants in pituitary tumor pathogenesis.