Ovarian Tumorigenesis in Mice Transgenic for Murine Inhibin α Subunit Promoter-Driven Simian Virus 40 T-Antigen: Ontogeny, Functional Characteristics, and Endocrine Effects1

Rahman, Nafis; Huhtaniemi, Ilpo

doi:10.1095/biolreprod64.4.1122

Cited by 18 publications

(15 citation statements)

References 46 publications

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“…27) or a mouse granulosa cell line (designated KK-1, see Ref. 28). The data presented in Table 2 show that most of the [ 125 I]hFSH internalized in these two cell types is also released back into the medium in an undegraded form rather than as degraded hormone.…”

Section: Fate Of the Internalized Hfshmentioning

confidence: 99%

Postendocytotic Trafficking of the Follicle-Stimulating Hormone (FSH)-FSH Receptor Complex

Krishnamurthy

Kishi

Shi

et al. 2003

Molecular Endocrinology

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Although the fates of the internalized hormone-receptor complexes formed by the lutropin/choriogonadotropin and the TSH receptors have been examined in some detail, much less is known about the fate of the internalized FSH-FSH receptor (FSHR) complex. Using biochemical and imaging approaches we show here that the majority of the internalized FSH-FSHR complex accumulates in endosomes and subsequently recycles back to the cell surface where the bound, intact hormone dissociates back into the medium. Only small amounts of FSH and the FSHR are routed to a lysosomal degradation pathway, and the extent of FSH-induced down-regulation of the cell surface and total FSHR is minimal. This pathway was detected in heterologous (human kidney 293T) cells transfected with the rat (r) or human (h) FSHR as well as in a mouse Sertoli cell line (MSC-1) or a mouse granulosa cell line (KK-1) transfected with the rFSHR.Additional experiments using a series of C-terminal deletions of the rFSHR and the hFSHR showed that the recycling of the internalized FSH-FSHR complex and the extent of hFSH-induced down-regulation is dictated by a short stretch of amino acids present at the extreme C-terminal end of the receptor.We conclude that most of the internalized FSH-FSHR complex is recycled back to the cell surface, that this recycling pathway is highly dependent on amino acid residues present near the C terminus of the FSHR, and that it is an important determinant of the extent of down-regulation of the FSHR.

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Section: Fate Of the Internalized Hfshmentioning

confidence: 99%

Postendocytotic Trafficking of the Follicle-Stimulating Hormone (FSH)-FSH Receptor Complex

Krishnamurthy

Kishi

Shi

et al. 2003

Molecular Endocrinology

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“…(This change was prompted by the fact that most suppliers are no longer offering Waymouth's MB752/l.) A transformed mouse granulosa cell line (designated KK-1, see Rahman & Huhtaniemi 2001) was provided by Dr I Huhtaniemi (Imperial College, London, UK). KK-1 cells were maintained in Dulbecco's modified Eagles' medium modified to contain 10 mM Hepes, 10% newborn calf serum and 50 µg/ml gentamicin.…”

Section: Plasmids and Cellsmentioning

confidence: 99%

The post-endocytotic fate of the gonadotropin receptors is an important determinant of the desensitization of gonadotropin responses

Bhaskaran¹,

Ascoli²

2005

Journal of Molecular Endocrinology

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Internalization of the ligand/receptor complexes is a consequence of the activation of the gonadotropin receptors. Since the recycling or degradation of the internalized receptors results in the maintenance or loss of cell surface receptors respectively and this contributes to the loss of responsiveness, we hypothesized that the fate of the internalized receptors could be an important component of desensitization. We examined this hypothesis using the wild-type and mutants of the human LH (hLHR) receptors and follitropin receptors expressed in MA-10 and KK-1 cells respectively. The receptor mutants were chosen because they are routed mostly to a lysosomal degradation pathway whereas the wild-type receptors are recycled back to the surface. We have shown that agonist stimulation of cells expressing the mutant receptors results in a more pronounced loss of cell surface receptors and agonist responses than stimulation of cells expressing the wild-type receptors. We concluded that receptor recycling promotes the maintenance of cell surface receptors and preserves hormonal responsiveness. This property of the hLHR is likely to be physiologically important because there at least two hLHR-expressing tissues in pregnant women, the maternal corpus luteum and the fetal Leydig cells, where a loss of hormonal responsiveness induced by the elevated levels of human chorionic gonadotropin that occur during pregnancy is not desirable.

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“…In intact inhα/Tag mice, serum progesterone and inhibin B levels rise and those of gonadotropins decrease, along with the ovarian tumor progression (22, 26). After the 3.5‐mo rhZP3 immunizations, serum progesterone was significantly decreased in both treatment groups, compared to nontreated and vehicle‐treated controls ( P <0.05; Fig.…”

Section: Resultsmentioning

confidence: 99%

A novel treatment strategy for ovarian cancer based on immunization against zona pellucida protein (ZP) 3

et al. 2011

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We tested the principle of treating malignant ovarian tumors by vaccination against their ectopically expressed protein, zona pellucida glycoprotein (ZP) 3, using as the experimental model the granulosa cell tumors that develop in transgenic mice expressing the simian virus 40 T-antigen under the inhibin-α promoter (inhα/Tag). We found high ZP3 expression in granulosa cell tumors of the transgenic mice, in human surface ovarian cancer and granulosa cell lines, and in human granulosa cell tumors and their metastases. Early preventive immunization (between 2 and 5.5 mo of age) of transgenic mice with recombinant human (rh) ZP3 prevented ovarian tumorigenesis, and delayed therapeutic immunization (between 4.5 and 7 mo) reduced weights of existing tumors by 86 and 75%, respectively (P<0.001), compared to vehicle-treated control mice. No objective side effects of the immunizations were observed. Liver metastases were found in nontreated/vehicle-treated controls (n=7/39), but none following active rhZP3 immunizations (n=0/36; P<0.05). Immunization with rhZP3 was highly effective, as demonstrated by the induction of anti-ZP3 antibodies, as well as proliferative responses to the ZP3 antigen. These results signal rhZP3 immunization as a novel strategy to be developed for the immunotherapy of ovarian granulosa cell tumors, as well as for that of other malignancies that may express ZP3.

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Ovarian Tumorigenesis in Mice Transgenic for Murine Inhibin α Subunit Promoter-Driven Simian Virus 40 T-Antigen: Ontogeny, Functional Characteristics, and Endocrine Effects1

Cited by 18 publications

References 46 publications

Postendocytotic Trafficking of the Follicle-Stimulating Hormone (FSH)-FSH Receptor Complex

Postendocytotic Trafficking of the Follicle-Stimulating Hormone (FSH)-FSH Receptor Complex

The post-endocytotic fate of the gonadotropin receptors is an important determinant of the desensitization of gonadotropin responses

A novel treatment strategy for ovarian cancer based on immunization against zona pellucida protein (ZP) 3

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