Identification of a novel transforming growth factor-beta (TGF-beta6) gene in fish: regulation in skeletal muscle by nutritional state.

Background: The transforming growth factor-beta (TGF-beta) family constitutes of dimeric proteins that regulate the growth, differentiation and metabolism of many cell types, including that of skeletal muscle in mammals. The potential role of TGF-betas in fish muscle growth is not known.

Results: Here we report the molecular characterization, developmental and tissue expression and regulation by nutritional state of a novel TGF-beta gene from a marine fish, the gilthead sea bream Sparus aurata.

Differentially expressed nucleolar transforming growth factor-beta1 target (DENTT) exhibits an inhibitory role on tumorigenesis.

Differentially expressed nucleolar transforming growth factor-beta1 target (DENTT), also known as testis-specific protein Y-encoded-like (TSPYL-2) and cell division autoantigen-1, is a member of the testis-specific protein Y-encoded (TSPY)/TSPY-L/SET/nucleosome assembly protein-1 superfamily. DENTT is expressed in various tissues including normal human lung. Here, we investigate the involvement of DENTT in cancer promotion and progression.

Modulation of tumor induction and progression of oncogenic K-ras-positive tumors in the presence of TGF- b1 haploinsufficiency.

Oncogenic K-ras is one of the most common genetic alterations in human lung adenocarcinomas. In addition, inactivation of clusters of tumor suppressor genes is required to bring about classical characteristics of cancer including angiogenesis as a prelude to invasion and metastasis. Transforming growth factor-beta (TGF-beta) 1 is a tumor suppressor gene that is implicated in lung cancer progression.

Transforming growth factor-beta in cancer and metastasis.

Transforming growth factor-beta (TGF-beta) is a multifunctional regulatory polypeptide that is the prototypical member of a large family of cytokines that controls many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival. The actions of TGF-beta are dependent on several factors including cell type, growth conditions, and the presence of other polypeptide growth factors. One of the biological effects of TGF-beta is the inhibition of proliferation of most normal epithelial cells using an autocrine mechanism of action, and this suggests a tumor suppressor role for TGF-beta.

Bombesin/gastrin-releasing peptide receptor antagonists increase the ability of histone deacetylase inhibitors to reduce lung cancer proliferation.

The effects of a bombesin/gastrin releasing peptide (BB/GRP) receptor antagonist, PD176252, and histone deacetylase (HDAC) inhibitor, MS-275, were investigated on human lung cancer cell lines. Using the MTT assay, PD176252 and MS-275 inhibited the proliferation of NCI-H1299 cells with IC50 values of 7 and 5 microg/mL, respectively. Using MS-275 and PD176252 together, the ability to inhibit lung cancer cellular growth increased significantly.

Differentially expressed nucleolar TGF-beta1 target (DENTT) shows tissue-specific nuclear and cytoplasmic localization and increases TGF-beta1-responsive transcription in primates.

Differentially Expressed Nucleolar TGF-beta1 Target (DENTT) is a new member of the TSPY/TSPY-like/SET/NAP-1 (TTSN) superfamily whose mRNA is induced by TGF-beta1 in TGF-beta1-responsive human lung cancer cells. Monkey DENTT mRNA contains a 2085-bp open reading frame that encodes a predicted polypeptide of 695 amino acids with five nuclear localization signals, two coiled-coil regions, and a domain that shows significant identity to a region that defines the TTSN superfamily. RT-PCR amplification and Western blot analyses showed DENTT mRNA and protein in adult monkey tissues, including the adrenal gland, cerebral cortex, and ovary.

Nkx2.1 transcription factor in lung cells and a transforming growth factor-beta1 heterozygous mouse model of lung carcinogenesis.

The Nkx2.1 homeobox gene and transforming growth factor-beta1 (TGF-beta1) are essential for organogenesis and differentiation of the mouse lung. NKX2.

Depressed adrenomedullin in the embryonic transforming growth factor-beta1 null mouse becomes elevated postnatally.

Transforming growth factor-beta (TGF-beta) and adrenomedullin are multifunctional regulatory proteins which are expressed in developing embryonic and adult tissues. Because of their colocalization, TGF-beta1 and adrenomedullin may be able to coordinately act to influence development and differentiation. In order to learn more about the biology of adrenomedullin in the absence of the effects of TGF-beta1 in vivo, we examined adrenomedullin in the TGF-beta1 null mouse.

Reversal of liver fibrosis in aryl hydrocarbon receptor null mice by dietary vitamin A depletion.

Aryl hydrocarbon receptor (AHR)-null mice display a liver fibrosis phenotype that is associated with a concomitant increase in liver retinoid concentration, tissue transglutaminase type II (TGaseII) activity, transforming growth factor beta (TGF beta) overexpression, and accumulation of collagen. To test the hypothesis that this phenotype might be triggered by the observed increase in liver retinoid content, we induced the condition of retinoid depletion by feeding AHR-null mice a vitamin A- deficient diet with the purpose to reverse the phenotype. Liver retinoid content decreased sharply within the first few weeks on the retinoid-deficient diet.

Serum levels of surfactant protein D are increased in mice with lung tumors.

Most murine lung tumors are composed of differentiated epithelial cells. We have reported previously that surfactant protein (SP)-D is expressed in urethane-induced tumors. Serum levels of SP-D are increased in patients with interstitial lung disease and acute respiratory distress syndrome and in rats with acute lung injury but have not been measured in mice.

Differential induction of early response genes by adrenomedullin and transforming growth factor-beta1 in human lung cancer cells.

Adrenomedullin (AM) is a hypotensive polypeptide that has been shown to stimulate cyclic AMP and intracellular free Ca2+ agents that are known to induce expression of proto-oncogenes, in various cell types. Transforming growth factor-beta 1 (TGF-beta1) is a multifunctional polypeptide that regulates proliferation, differentiation and cell cycle progression in both normal and malignant epithelial cells. The diverse biological actions of AM and TGF-beta1 may be related to their capacities to initiate different genomic programs in target cells via the induction of expression of multiple genes including early response genes and proto-oncogenes.

Expression of differentially expressed nucleolar transforming growth factor-beta1 target (DENTT) in adult mouse tissues.

Differentially expressed nucleolar TGF-beta1 target (DENTT) is a novel member of the TSPY/TSPY-L/SET/NAP-1 (TTSN) superfamily that we have previously identified in human lung cancer cells. Here, we have investigated the expression of this protein in the adult mouse. By Western analysis, DENTT is highly expressed in the pituitary gland and moderately in the adrenals, brain, testis, and ovary.

Heterozygous inactivation of TGF-beta1 increases the susceptibility to chemically induced mouse lung tumorigenesis independently of mutational activation of K-ras.

Mice heterozygous for deletion of the transforming growth factor beta1 (TGF-beta1) gene show an enhanced rate of lung tumorigenesis following carcinogen treatment. Since the growth inhibitory activity of TGF-beta1 in epithelial cells is associated with K-ras p21, and K-ras mutations commonly occur in chemically-induced mouse lung tumors, we postulated that tumors in heterozygous TGF-beta1 mice might be more likely to have K-ras mutations compared with tumors in wildtype TGF-beta1 mice. Urethane-induced lung tumors in AJBL6 TGF-beta1 +/- and +/+ mice were examined for K-ras mutations by polymerase chain reaction/single strand conformation polymorphism analysis and sequencing.

Indomethacin reduces lung adenoma number in A/J mice.

The effects of indomethacin on A/J mice were investigated. The non-steroidal antiinflammatory drug (NSAID) indomethacin reduced significantly the number of lung adenomas 3, 4 or 8 months after urethane injection by 28, 30 and 29% respectively. The density of apoptotic cell bodies increased 2.

Identification of differentially expressed nucleolar TGF-beta1 target (DENTT) in human lung cancer cells that is a new member of the TSPY/SET/NAP-1 superfamily.

The transforming growth factor-beta1 (TGF-beta1) responsive epithelial non-small-cell lung cancer (NSCLC) cell line NCI-H727 was used to identify potential target genes involved in TGF-beta1-mediated responses. Comparative cDNA expression patterns between cells treated with TGF-beta1 and those treated with vehicle were generated by differential mRNA display. One 496-bp fragment, differentially increased threefold by TGF-beta1 and hybridizing to a 2.

Transforming growth factor-beta 1 and its receptors in human lung cancer and mouse lung carcinogenesis.

The transforming growth factor-betas (TGF-beta s) are multifunctional proteins that inhibit the proliferation of many epithelial cells through a set of cell protein receptors that includes the TGF-beta type I (RI) and type II (RII) receptors. Loss of growth inhibition by TGF-beta is thought to contribute to the development of many types of tumors. In the present study, we have examined expression of the proteins and mRNAs for TGF-beta 1, TGF-beta RI, and TGF-beta RII in normal human lung, well-characterized non-small cell lung cancer (NSCLC) cell lines, and primary NSCLC specimens.

Prostaglandin E2 and vasoactive intestinal peptide increase vascular endothelial cell growth factor mRNAs in lung cancer cells.

The effects of prostaglandin E2 (PGE2) and vasoactive intestinal peptide (VIP) on vascular endothelial cell growth factor (VEGF) mRNAs were investigated using lung cancer cells. By RT-PCR, VEGF(121), VEGF(165), and VEGF(189), but not VEGF(206) isoforms were detected in all lung cancer cell lines and biopsy specimens examined. By Northern blot, VEGF mRNA was detected in all small cell lung cancer (SCLC) and non-SCLC (NSCLC) cell lines examined.

Retinoic acid down-regulates VPAC(1) receptors and TGF-beta 3 but up-regulates TGF-beta 2 in lung cancer cells.

The effects of retinoic acid (RA) on lung cancer cells were investigated. Both all-trans (t-RA) and 13-cis RA (c-RA) decreased specific (125)I-VIP binding to NCI-H1299 cells in a time- and concentration-dependent manner. After 20 hr, 30 microM t-RA decreased specific (125)I-VIP binding by 60%.

Enhanced tumorigenesis and reduced transforming growth factor-beta type II receptor in lung tumors from mice with reduced gene dosage of transforming growth factor-beta1.

To elucidate the role of transforming growth factor-beta1 (TGF-beta1) and the TGF-beta type II receptor (TGF-beta RII) as tumor-suppressor genes in lung carcinogenesis, we mated C57BL/6 mice heterozygous (HT) for deletion of the TGF-beta1 gene with A/J mice to produce AJBL6 TGF-beta1 HT progeny and their wild-type (WT) littermates. Immunohistochemical staining, in situ hybridization, and northern blot analyses showed lower staining and hybridization for TGF-beta1 protein and mRNA, respectively, in the lungs of normal HT mice versus WT mice. Competitive reverse transcription-polymerase chain reaction (CRT-PCR) amplification showed the level of TGF-beta1 mRNA in the lungs of HT mice to be fourfold lower than the level in WT lung.

The metabolism of BW2258U89, a GRP receptor antagonist.

BW2258U89 is a gastrin releasing peptide (GRP) receptor antagonist which inhibits the proliferation of the neuroendocrine tumor small cell lung cancer (SCLC). Here the biological activity of BW2258U89 and its metabolite were investigated. Using mass spectroscopy (LC-ESI/MS) techniques, three major peaks for BW2258U89 were observed with mass/charge (m/z) ratios of 1081.