Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk (original) (raw)
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Endocrinology, 2007
Pituitary tumors are common intracranial neoplasms that often result in endocrine dysfunction due to hormone overproduction or deficiencies from mass effects. Gonadotrope cell or gonadotropinomas are tumors that produce LH and/or FSH and represent 40% of macroadenomas. Little is known about their underlying pathogenic mechanisms. We compared expression profiles of 10 gonadotropinomas with nine normal pituitaries by cDNA array and identified bone morphogenetic protein- and retinoic acid-inducible neural-specific protein-3 (BRINP3) as overexpressed in tumors, compared with normals. BRINP3 is a novel, normally brain restricted protein of unknown function. BRINP3 mRNA was expressed selectively in gonadotropinomas. Subcellular localization studies showed that BRINP3 was targeted to the mitochondria, but BRINP3 overexpression was unable to protect pituitary cells against programmed cell death induced by growth factor withdrawal. However, BRINP3 overexpression in pituitary gonadotrope cell...
Pituitary tumors: Cell type-specific roles for BMP4
Molecular and Cellular Endocrinology, 2010
BMP-4 plays a crucial role not only in the formation of the anterior pituitary during embryo development but also in the pathogenesis of pituitary tumors in adults. In tumor cells, BMP-4 promotes prolactin secretion and lactotroph cell proliferation through a Smad-estrogen receptor crosstalk but it inhibits ACTH production and cell proliferation of corticotrophs. In addition, BMP-4 increases GH secretion in rat pituitary tumor somatolactotroph GH3 cells and FSHβ subunit gene transcription in the murine gonadotroph cell line, LβT2. Therefore, BMP-4 has a differential role on different types of pituitary tumors: it promotes pituitary prolactinoma while it inhibits corticotroph pathogenesis in Cushing's disease. The modulation of BMP-4 also plays an important role in the therapeutic mechanism of action of bromocriptine, somatostatin analogs and retinoic acid.
A pituitary gene encodes a protein that produces differentiation of breast and prostate cancer cells
Proceedings of the National Academy of Sciences, 2004
A cDNA clone of 1.1 kb encoding a 108-aa polypeptide was isolated from a human pituitary cDNA library by expression cloning. This protein was named tumor differentiation factor (TDF). The recombinant TDF protein and a 20-aa peptide, P1, selected from the ORF of the gene, induced morphological and biochemical changes consistent with differentiation of human breast and prostate cancer cells. Fibroblast, kidney, hepatoma, and leukemic lymphocytic cell lines were unaffected. Breast and prostate cancer cells aggregated in spheroid-like structures within 24 h of exposure to TDF. This effect was abrogated by a specific affinity-purified rabbit polyclonal anti-P1 Ab. E-cadherin expression was increased in a dose-dependent manner by TDF. Treatment of MCF7 cells with TDF led to production of a lactalbumin-related protein. Peptide P1 significantly decreased the growth of androgen-independent DU145 prostate cancer in severe combined immunodeficient mice. The presence of TDF protein in human ser...
Cancer Biology & Therapy, 2011
Background Gonadotrophic pituitary adenoma is a major subtype of pituitary adenoma in the sellar region, but it is rarely involved in the hypersecretion of hormones into blood; thus, it is commonly regarded as "non-functioning. " Its tumorigenic mechanisms remain unknown. The aim of this study was to identify human gonadotrophic pituitary adenoma stem cells (hPASCs) and explore the underlying gene expression profiles. In addition, the potential candidate genes involved in the invasive properties of pituitary adenoma were examined. Methods The hPASCs from 14 human gonadotrophic pituitary adenoma clinical samples were cultured and verified via immunohistochemistry. Genetic profiling of hPASCs and the matched tumor cells was performed through RNA-sequencing and subjected to enrichment analysis. By aligning the results with public databases, the candidate genes were screened and examined in invasive and non-invasive gonadotrophic pituitary adenomas using Real-time polymerase chain reaction. Results The hPASCs were successfully isolated and cultured from gonadotrophic pituitary adenoma in vitro, which were identified as positive for generic stem cell markers (Sox2, Oct4, Nestin and CD133) via immunohistochemical staining. The hPASCs could differentiate into the tumor cells expressing follicle-stimulating hormone in the presence of fetal bovine serum in the culture medium. Through RNA-sequencing, 1352 differentially expressed genes were screened and identified significantly enriched in various gene ontologies and important pathways. The expression levels of ANXA2, PMAIP1, SPRY2, C2CD4A, APOD, FGF14 and FKBP10 were significantly upregulated while FNDC5 and MAP3K4 were downregulated in the invasive gonadotrophic pituitary adenomas compared to the non-invasive ones. Conclusion Genetic profiling of hPASCs may explain the tumorigenesis and invasiveness of gonadotrophic pituitary adenoma. ANXA2 may serve as a potential therapeutic target for the treatment of gonadotrophic pituitary adenoma.
Genetics and proteomics of pituitary tumors
Endocrine, 2005
Genetics and proteomics determine structure and function of normal tissues, and the molecular alterations that underlie tumorigenesis result in changes in these aspects of tissue biology in neoplasms. We review the known genetic alterations in pituitary tumors. These include the oncogenic Gsa a a a a protein (GSP)-activating mutations, and pituitary tumor-derived fibroblast growth factor receptor-4 (ptd-FGFR4), as well as tumor suppressor gene mutations associated with multiple endocrine neoplasia type 1 (MEN1). Other candidates identified from expression profiling include pituitary tumortransforming gene (PTTG), GADD45, and bone morphogenic protein (BMP)4. Proteomic changes in pituitary tumors include classical alterations identified by immunohistochemistry as well as epigenetic reductions in p27. The underlying mechanisms for dysregulated cell adhesive molecules including cadherins and FGFRs are reviewed. The combined use of genetic and proteomic approaches will enhance novel drug therapeutic development.
Endocrinology, 2013
Retinoic acid (RA)-induced expression of bone morphogenetic protein-4 (BMP-4) inhibits in vitro and in vivo cell proliferation and ACTH synthesis in corticotroph-derived tumor cells. Reduced expression of BMP-4 in this adenoma subtype is associated with epigenomic silencing, and similar silencing mechanisms are also associated with the RA-responsive dopamine D2 receptor (D2R) in somatolactotroph cells. We now show that preincubation with the epidrugs zebularine and trichostatin A is obligate and permissive for RA-induced expression of the BMP-4 and the D2R genes in pituitary tumor cells. Combined epidrug challenges are associated with marginal reduction in CpG island methylation. However, significant change to histone tail modifications toward those associated with expression-competent genes is apparent, whereas RA challenge alone or in combined incubations does not have an impact on these modifications. Epidrug-mediated and RAaugmented expression of endogenous BMP-4 increased or decreased cell proliferation and colonyforming efficiency in GH3 and AtT-20 pituitary tumor cells, respectively, recapitulating recent reports of challenges of these cells with exogenous ligand. The specificity of the BMP-4 -mediated effects was further supported by knock-down experiments of the BMP-4 antagonist noggin (small interfering RNA [siRNA]). Knock-down of noggin, in the absence and the presence of epidrugs, induced and augmented BMP-4 expression, respectively. In cell proliferation assays, challenge with either epidrugs or siRNA led to significant increase in cell numbers at the 72-hour time point; however, in siRNA-treated cells coincubated with epidrugs, a significant increase was apparent at the 48-hour time point. These studies show the potential of combined drug challenges as a treatment option, where epidrug renders silenced genes responsive to conventional therapeutic options.
Histochemistry and Cell Biology, 2004
The pituitary protein transcription factor (Pit-1) regulates the differentiation and proliferation of somatotrophs, lactotrophs, and thyrotrophs and the c-Myc oncoprotein plays a critical role in somatotroph and lactotroph differentiation. Both were involved in the genesis of pituitary tumors. The combined analysis of Pit-1 and c-Myc expression and the morphometric and biochemical parameters of the lactotroph population after treatment with estrogen for 7, 20, and 60 days provided new information on molecular mechanisms implicated in the formation of prolactinomas. Estrogen treatment for 7 days caused a significant proliferation of lactotrophs (70%) and this increase reached an additional 55% at 60 days. The proliferation of lactotrophs was concurrent with higher serum and pituitary prolactin levels. An augmentation of Pit-1 and c-Myc expression in both cytoplasmic and nuclear extracts after estrogen can be associated with lactotroph proliferation. Moreover, the multistep correlation analysis revealed that the expression of nuclear Pit-1 was the strongest predictor of prolactinoma development. Also the Pit-1 immunolocalization in nuclei of gonadotrophs suggests the activation of genes involved in transdifferentiation of gonadotroph to lactotroph. Therefore, the understanding of the Pit-1 function may help in the design of strategies to control the secretion and proliferation of pituitary tumors of the somatomammotrope lineage.
Regulated expression of the prolactin gene in rat pituitary tumor cells
Journal of Cell Biology, 1980
Prolactin (PRL) gene expression in three strains of GH cells (rat pituitary tumor cells) has been quantitated by measurement of: (a) intracellular and extracellular PRL, (b) cytoplasmic translatable PRL-specific mRNA (mRNAPRL), and (c) molecular hybridization of cytoplasmic poly(A) RNA to cDNAPRL (DNA complementary to mRNAPRL). Three GH cell lines utilized in this investigation were a PRL-producing (PRL+) strain, GH4C1, a PRL nonproducing 5-bromo-deoxyuridine resistnat (PRL- BrdUrdr) strain, F1BGH12C1, and a new strain, 928-9b, derived by fusion of PRL+ cells with a nuclear monolayer of the PRL-, BrdUrdr GH cell strain. PRL production is a characteristic of 928-9b cells, but the level of PRL production (2-4 micrograms/mg protein/24 h) is much lower than that of the PRL+ strain, GH4C1 (15-25 micrograms/mg protein/24 h). Levels of cytoplasmic translatable mRNAPRL and cytoplasmic PRL-RNA sequences quantitated with a cDNAPRL probe were also much lower in 928-9b as compared to the PRL+ p...
Molecular and cellular biology, 1982
GH3 cells normally synthesize and secrete two pituitary polypeptide hormones, prolactin and growth hormone. From an ethyl methane sulfonate-mutagenized population, prolactin low-producing variants have been isolated at a frequency near 20%. Intracellular prolactin synthesis in the variants was reduced 40- to 100-fold compared to wild-type cells while growth hormone synthesis varied less than 2-fold. This decrease was paralleled by a decrease in intracellular preprolactin mRNA. Although reduced, prolactin synthesis was still repressible by glucocorticoids. There was a coordinate loss of expression of p21, a thyroid and glucocorticoid hormone-regulated protein, in GH3 cells, whereas the synthesis and regulation of other hormonally responsive proteins were unimpaired in the variants. Since p21 expression was coordinately regained in a high-producing prolactin revertant cell, expression of the two proteins is tightly coupled in GH3 cells. The stability of the low-producing phenotype dif...