Genetic evidence that SMAD2 is not required for gonadal tumor development in inhibin-deficient mice
- PDF / 3,336,807 Bytes
- 9 Pages / 595 x 794 pts Page_size
- 106 Downloads / 219 Views
Open Access
RESEARCH
Genetic evidence that SMAD2 is not required for gonadal tumor development in inhibin-deficient mice Research
Saneal Rajanahally1,4, Julio E Agno1, Roopa L Nalam1,2, Michael B Weinstein5, Kate L Loveland6, Martin M Matzuk1,2,3 and Qinglei Li*1
Abstract Background: Inhibin is a tumor-suppressor and activin antagonist. Inhibin-deficient mice develop gonadal tumors and a cachexia wasting syndrome due to enhanced activin signaling. Because activins signal through SMAD2 and SMAD3 in vitro and loss of SMAD3 attenuates ovarian tumor development in inhibin-deficient females, we sought to determine the role of SMAD2 in the development of ovarian tumors originating from the granulosa cell lineage. Methods: Using an inhibin α null mouse model and a conditional knockout strategy, double conditional knockout mice of Smad2 and inhibin alpha were generated in the current study. The survival rate and development of gonadal tumors and the accompanying cachexia wasting syndrome were monitored. Results: Nearly identical to the controls, the Smad2 and inhibin alpha double knockout mice succumbed to weight loss, aggressive tumor progression, and death. Furthermore, elevated activin levels and activin-induced pathologies in the liver and stomach characteristic of inhibin deficiency were also observed in these mice. Our results indicate that SMAD2 ablation does not protect inhibin-deficient females from the development of ovarian tumors or the cachexia wasting syndrome. Conclusions: SMAD2 is not required for mediating tumorigenic signals of activin in ovarian tumor development caused by loss of inhibin. Background The transforming growth factor β (TGFβ) superfamily ligands including activins and inhibins play integral roles in a wide variety of developmental processes [1-3]. Inhibins are α and β subunit heterodimers (inhibin A: α, βA; inhibin B: α, βB) that oppose activin signaling by antagonizing activin receptors (ACVRs), whereas activins are homodimers (activin A, βA: βA; activin B, βB: βB) or heterodimers (activin AB, βA: βB) of the β subunits [4-6]. Activin signal transduction is initiated when the ligand binds to its type 2 serine/threonine kinase receptor which in turn phosphorylates the type 1 receptor [7-11]. The type 1 receptor then phosphorylates and activates receptor-regulated SMADs (R-SMADs; SMAD2 and SMAD3), * Correspondence: [email protected] 1
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA
which subsequently form complexes with the common SMAD, SMAD4. The R-SMADs/SMAD4 can translocate into the nucleus to regulate gene expression via recruitment of specific transcription factors, activators, and repressors [12-15]. Activins and inhibins are expressed in ovarian granulosa cells and were first described for their roles in FSH regulation [16,17]. However, subsequent studies demonstrated the involvement of these ligands in multiple developmental and pathological events including carcinogenesis [18-20]. Inhibin is a tumor suppressor [21], as inhibin α
