Abstract
Molecular changes that give rise to granulosa cell tumors of the ovary are not well understood. Previously, we showed that deletion in granulosa cells of the bone morphogenetic protein receptor-signaling transcription factors, Smad1 and Smad5, causes development of metastatic granulosa cell tumors that phenocopy the juvenile form of granulosa cell tumors (JGCTs) in humans. The TGFβ-SMAD2/3 pathway is active in JGCTs, but its role is unknown. We tested the in vivo contribution of TGFβ-SMAD signaling to JGCT development by genetically deleting the common Smad4 from Smad1/5 double knockout mice. Smad1/5/4 triple knockout mice were sterile and had significantly increased survival and delayed tumor development compared to those for the Smad1/5 double knockout mice. The few tumors that did develop were smaller, showed no evidence of metastasis, and had increased apoptosis. In the human JGCT cell line COV434, TGFβ1 increased viability by inhibiting apoptosis through a TGFβ type I receptor-dependent repression of caspase activity and inhibition of poly(ADP-ribose) polymerase cleavage. These data support a tumor-promoting function of TGFβ in JGCTs through its ability to repress apoptosis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics*
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Carcinogenesis / genetics*
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Carcinogenesis / pathology
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Cell Survival / genetics
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Female
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Granulosa Cell Tumor / genetics
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Granulosa Cell Tumor / metabolism
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Granulosa Cell Tumor / pathology
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Granulosa Cells / metabolism*
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Granulosa Cells / pathology*
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction / genetics
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Smad Proteins / genetics
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Smad Proteins / metabolism
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Transforming Growth Factor beta1 / genetics*
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Transforming Growth Factor beta1 / metabolism*
Substances
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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Transforming Growth Factor beta1
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Poly(ADP-ribose) Polymerases
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I