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Constitutively active transforming growth factor ? receptor 1 in the mouse ovary promotes tumorigenesis.

ABSTRACT: Despite the well-established tumor suppressive role of TGF? proteins, depletion of key TGF? signaling components in the mouse ovary does not induce a growth advantage. To define the role of TGF? signaling in ovarian tumorigenesis, we created a mouse model expressing a constitutively active TGF? receptor 1 (TGFBR1) in ovarian somatic cells using conditional gain-of-function approach. Remarkably, these mice developed ovarian sex cord-stromal tumors with complete penetrance, leading to reproductive failure and mortality. The tumors expressed multiple granulosa cell markers and caused elevated serum inhibin and estradiol levels, reminiscent of granulosa cell tumors. Consistent with the tumorigenic effect, overactivation of TGFBR1 altered tumor microenvironment by promoting angiogenesis and enhanced ovarian cell proliferation, accompanied by impaired cell differentiation and dysregulated expression of critical genes in ovarian function. By further exploiting complementary genetic models, we substantiated our finding that constitutively active TGFBR1 is a potent oncogenic switch in mouse granulosa cells. In summary, overactivation of TGFBR1 drives gonadal tumor development. The TGFBR1 constitutively active mouse model phenocopies a number of morphological, hormonal, and molecular features of human granulosa cell tumors and are potentially valuable for preclinical testing of targeted therapies to treat granulosa cell tumors, a class of poorly defined ovarian malignancies.

SUBMITTER: Gao Y

PROVIDER: S-EPMC5173031 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Constitutively active transforming growth factor β receptor 1 in the mouse ovary promotes tumorigenesis.

Gao Yang Y Vincent David F DF Davis Anna Jane AJ Sansom Owen J OJ Bartholin Laurent L Li Qinglei Q

Oncotarget 20160701 27

Despite the well-established tumor suppressive role of TGFβ proteins, depletion of key TGFβ signaling components in the mouse ovary does not induce a growth advantage. To define the role of TGFβ signaling in ovarian tumorigenesis, we created a mouse model expressing a constitutively active TGFβ receptor 1 (TGFBR1) in ovarian somatic cells using conditional gain-of-function approach. Remarkably, these mice developed ovarian sex cord-stromal tumors with complete penetrance, leading to reproductive ...[more]

PMID: 27344183

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Project description:BACKGROUND:The simplicity of Transforming Growth Factor ß (TGF?) signaling pathway, linear and non-amplified, hardly sustains its variety of responses. This is often justified by the complex regulation showed by Smad proteins, TGF? signaling intracellular transducers, object of post-translational modifications that modulate TGF?-dependent transcription. Protein acetylation is emerging as a compelling mechanism affecting the activities of significant transcription factors, including p53, FOXO or NF-kB. Smad proteins might be controlled by this mechanism, implying that accessory factors capable of altering Smads-transcriptional complexes acetylation status and hence regulate TGF? responses remain to be identified. Understanding this interaction may help in the assessment of TGF? signaling outcomes, extending from healthy physiology to pathological conditions and cancer. METHODS:A two-hybrid chimera interacting system allowed to identify Sirt1, a NAD+ dependent type III histone deacetylase, as a novel Smad2 interactor. Several well stablished cellular models were applied to characterize this interaction by means of co-immunoprecipitation of tagged proteins and immuno-fluorescence staining. The occurrence of the interaction at Smad2 driven transcriptomic complexes was studied by means of DNA-pull-down and chromatin immunoprecipitation (ChIP), while its effects were assessed by protein over-expression and siRNA applied into a TGF?-dependent reporter gene assay. RESULTS:The interaction was confirmed and observed to be enhanced upon Smad2 acetylation, a known feature of active and nuclear Smad2. However, Sirt1 did not play a major role in Smad2 deacetylation. Anti-Sirt1 ChIP showed increased recovery of promoter regions corresponding to Smad2-driven genes after TGF?-stimulation, while its occurrence at Smad2-dependent transcriptomic complexes on DNA was found to effectively modulate gene expression. CONCLUSIONS:Sirt1 presence on Smad2-driven TGF?-dependent regulatory elements was detected and found to increase after TGF? treatment. Moreover, Sirt1 overexpression resulted in a decrease of the activity of a Smad2-driven TGF?-dependent reporter gene, while Sirt1 interference increased its activity. This would confirm the relevance of the discovered Sirt1-Smad2 interaction for the regulation of TGF?-dependent gene transcription.

Dataset Information

Constitutively active transforming growth factor ? receptor 1 in the mouse ovary promotes tumorigenesis.

Publications

Constitutively active transforming growth factor β receptor 1 in the mouse ovary promotes tumorigenesis.

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