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Sex differences in the pituitary transforming growth factor-?1 system: studies in a model of resistant prolactinomas.

ABSTRACT: Dopamine and estradiol interact in the regulation of lactotroph cell proliferation and prolactin secretion. Ablation of the dopamine D2 receptor gene (Drd2(-/-)) in mice leads to a sexually dimorphic phenotype of hyperprolactinemia and pituitary hyperplasia, which is stronger in females. TGF-?1 is a known inhibitor of lactotroph proliferation. TGF-?1 is regulated by dopamine and estradiol, and it is usually down-regulated in prolactinoma experimental models. To understand the role of TGF-?1 in the gender-specific development of prolactinomas in Drd2(-/-) mice, we compared the expression of different components of the pituitary TGF-?1 system, including active cytokine content, latent TGF-?-binding protein isoforms, and possible local TGF-?1 activators, in males and females in this model. Furthermore, we evaluated the effects of dopamine and estradiol administration to elucidate their role in TGF-?1 system regulation. The expression of active TGF-?1, latent TGF-?-binding protein isoforms, and several putative TGF-?1 activators evaluated was higher in male than in female mouse pituitary glands. However, Drd2(-/-) female mice were more sensitive to the decrease in active TGF-?1 content, as reflected by the down-regulation of TGF-?1 target genes. Estrogen and dopamine caused differential regulation of several components of the TGF-?1 system. In particular, we found sex- and genotype- dependent regulation of active TGF-?1 content and a similar expression pattern for 2 of the putative TGF-?1 activators, thrombospondin-1 and kallikrein-1, suggesting that these proteins could mediate TGF-?1 activation elicited by dopamine and estradiol. Our results indicate that (1) the loss of dopaminergic tone affects the pituitary TGF-?1 system more strongly in females than in males, (2) males express higher levels of pituitary TGF-?1 system components including active cytokine, and (3) estradiol negatively controls most of the components of the system. Because TGF-?1 inhibits lactotroph proliferation, we propose that the higher levels of the TGF-?1 system in males could protect or delay the development of prolactinomas in Drd2(-/-) male mice.

SUBMITTER: Recouvreux MV

PROVIDER: S-EPMC3800752 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Sex differences in the pituitary transforming growth factor-β1 system: studies in a model of resistant prolactinomas.

Recouvreux M Victoria MV Lapyckyj Lara L Camilletti M Andrea MA Guida M Clara MC Ornstein Ana A Rifkin Daniel B DB Becu-Villalobos Damasia D Díaz-Torga Graciela G

Endocrinology 20130905 11

Dopamine and estradiol interact in the regulation of lactotroph cell proliferation and prolactin secretion. Ablation of the dopamine D2 receptor gene (Drd2(-/-)) in mice leads to a sexually dimorphic phenotype of hyperprolactinemia and pituitary hyperplasia, which is stronger in females. TGF-β1 is a known inhibitor of lactotroph proliferation. TGF-β1 is regulated by dopamine and estradiol, and it is usually down-regulated in prolactinoma experimental models. To understand the role of TGF-β1 in t ...[more]

PMID: 24008346

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Project description:Transforming growth factor-beta (TGF-β), a member of the TGF-β cytokine superfamily, is known to bind to sulfated glycosaminoglycans (GAGs), but the nature of this interaction remains unclear. In a recent study, we found that preterm human milk TGF-β2 is sequestered by chondroitin sulfate (CS) in its proteoglycan form. To understand the molecular basis of the TGF-β2-CS interaction, we utilized the computational combinatorial virtual library screening (CVLS) approach in tandem with molecular dynamics (MD) simulations. All possible CS oligosaccharides were generated in a combinatorial manner to give 24 di- (CS02), 192 tetra- (CS04), and 1536 hexa- (CS06) saccharides. This library of 1752 CS oligosaccharides was first screened against TGF-β2 using the dual filter CVLS algorithm in which the GOLDScore and root-mean-square-difference (RMSD) between the best bound poses were used as surrogate markers for in silico affinity and in silico specificity. CVLS predicted that both the chain length and level of sulfation are critical for the high affinity and high specificity recognition of TGF-β2. Interestingly, CVLS led to identification of two distinct sites of GAG binding on TGF-β2. CVLS also deduced the preferred composition of the high specificity hexasaccharides, which were further assessed in all-atom explicit solvent MD simulations. The MD results confirmed that both sites of binding form stable GAG-protein complexes. More specifically, the highly selective CS chains were found to engage the TGF-β2 monomer with high affinity. Overall, this work present key principles of recognition with regard to the TGF-β2-CS system. In the process, it led to the generation of the in silico library of all possible CS oligosaccharides, which can be used for advanced studies on other protein-CS systems. Finally, the study led to the identification of unique CS sequences that are predicted to selectively recognize TGF-β2 and may out-compete common natural CS biopolymers.

Dataset Information

Sex differences in the pituitary transforming growth factor-?1 system: studies in a model of resistant prolactinomas.

Publications

Sex differences in the pituitary transforming growth factor-β1 system: studies in a model of resistant prolactinomas.

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