Disease relevance of NMB

• To assess NMB function, proliferation was determined in the nonmalignant human colonic epithelial cell line NCM-460 and in the colon cancer cell lines Caco-2 and HT-29 [1].
• Neuromedin B binds with high affinity, elevates cytosolic calcium and stimulates the growth of small-cell lung cancer cell lines [2].
• Evidence for autocrine actions of neuromedin B and gastrin-releasing peptide in non-small cell lung cancer [3].
• In this report, we demonstrate that both GRP and another member of the bombesin family of peptides, neuromedin B (NMB), are also autocrine growth factors for non-small cell lung carcinoma (NSCLC) [3].
• Particularly relevant is the BB3 expression in lung carcinoids and other neuroendocrine lung tumors, whereas gastrointestinal carcinoids preferably express NMB receptors [4].

Psychiatry related information on NMB

• CONCLUSION: The results suggest that NMB is a very strong candidate gene of eating behaviors and predisposition to obesity [5].
• In parallel, the suppressed social interaction elicited by intra-DRN administration of NMB was attenuated by a systemically administered 5-HT2C (but not 5-HT1A) receptor antagonist [6].

High impact information on NMB

• RESULTS: Neuromedin B and GRP receptor mRNAs were detected in human and rabbit colonic smooth muscle cells [7].
• The relative rank potency of bombesin-like peptides for this receptor was [Phe13]bombesin > [Leu13]bombesin > GRP > neuromedin B [8].
• Neuromedin B (NMB) is one of the bombesin (BN)-related peptides in mammals [9].
• The most potent immunotoxin, 14G2a.dgA, inhibited the protein synthesis of neuroblastoma cell lines IMR5 and NMB by 50% at concentrations of 6 x 10(-12) M [10].
• These data suggest that NMB may be a regulatory peptide in lung cancer [11].

Chemical compound and disease context of NMB

• GRP, the mammalian homolog of bombesin and its receptor, as well as NMB, the mammalian homolog of ranatensin, are expressed in human neoplasms and, in particular, in small cell lung carcinomas (SCLC) [12].
• Here we report the analysis of human AMPA and kainate receptor expression in four neuroblastoma cell lines (SK-N-MC, IMR-32, CHP 126 and NMB/N7) [13].
• We now show that VIP had mitogenic activity in a human neuroblastoma cell line (NMB), as measured by cell number and thymidine incorporation [14].
• We examined the profile of two bombesin (BN) antagonists, (CH3)2CHCO-His-Trp-Ala-Val-D-Ala-His-Leu-NHCH3] (ICI 216140) and [D-Phe6,des-Met14]BN(6-14)ethylamide (DPDM-BN EA), against neuromedin B-induced Ca2+ mobilization in the small cell lung cancer (SCLC) line NCI-H345 [15].

Biological context of NMB

• Results of 125I-[D-Tyr0]NMB displacement assays using unlabeled NMB for competition indicated that high affinity NMB binding was determined by amino acid sequences in transmembrane domain V (TM-V) of the NMB-R [16].
• Specific [125I-Tyr0]NMB binding was inhibited with high affinity by NMB (IC50 = 1 nM) and moderate affinity by bombesin, GRP and [D-Arg1, D-Pro2, D-Trp7,9, Leu11]substance P ([APTTL]SP) but not GRP1-16 (IC50 = 50, 100, 1,000 and > 10,000 nM, respectively) [2].
• Exogenously added NMB was 50-100% more efficacious than gastrin-releasing peptide in causing tumor cell proliferation, whereas only NMB increased NCM-460 cell proliferation [1].
• To determine whether NMB is a potential autocrine growth factor for lung tumors, NMB gene expression, peptide synthesis, and secretion have been investigated in a panel of SCLC and non-SCLC (NSCLC) cell lines [17].
• A missense mutation (p.P73T) located within the NMB gene showed significant associations with eating behaviors and obesity phenotypes [5].

Anatomical context of NMB

• In cancer, the amount of NMB was similar to that expressed by proliferating epithelial cells located within the crypt [1].
• In contrast, little is known about the bombesin-like peptide neuromedin B (NMB) and its receptor (NMB-R) in the human gastrointestinal tract [1].
• (177)Lu-AMBA also identified all NMB-expressing tumours, but did not detect BRS-3-expressing tumours or BRS-3-expressing pancreatic islets [18].
• Production of neuromedin B and neuromedin B gene expression in human lung tumor cell lines [17].
• The number of HT-29 cells, partially serum deprived (1% fetal bovine serum) for 48 h, was increased after 24 h of stimulation with bombesin, GRP, neuromedin B (NMB) and neuromedin C (NMC) ranging from 0.1 nM up to 1 microM [19].

Associations of NMB with chemical compounds

• The Ile216-->Ser substitution, however, abolished high affinity NMB binding and severely impaired the ability of the mutant receptor to stimulate NMB-dependent inositol phosphate formation [16].
• By immunoblotting using SDS-PAGE gradient gels fixed in trichloroacetic acid, GRP and NMB were found in fractions of culture medium that had been purified by high pressure liquid chromatography (HPLC) from NSCLC cell lines [3].
• The antiserum used in the GRP radioimmunoassay failed to cross-react with NMB but showed some cross-reactivity with amphibian phyllolitorin raising the possibility that certain SCLC cell lines may produce a phyllolitorin-like peptide [17].
• Sequence analysis revealed that NMB is encoded in a 76-amino acid precursor and ranatensin in an 82-amino acid precursor [20].
• Systematically replacing each residue with alanine, or changing its chirality, demonstrated that the carboxyl-terminal residues His8, Phe9, and Met10 of NMB are important for optimal activity [21].

Physical interactions of NMB

• The bombesin-related peptides neuromedin B (NMB) and phyllolitorin also bound to GRP receptors with Ki values of 22.7 and 59.1 nM respectively [22].

Regulatory relationships of NMB

• NMB induced a larger percent change in alkaline phosphatase secretion than GRP with a half maximal response at less than 1 nM NMB [23].
• Gastrin release from cultured cells of both tumors was suppressed by 0.1 and 10 nM neuromedin B and tended to be suppressed by 0.1-10 nM GRP-10 [24].
• The effect of NGF on the cytoskeleton could not be induced in other human cell lines like NMB or KTCTL-30 [25].
• Vasoactive intestinal peptide (VIP) stimulates the neuroblastoma cell line (NMB) to proliferate [26].
• NMB cells express neutral endopeptidase (NEP) activity that can be specifically inhibited by phosphoramidon (PA) [26].

Other interactions of NMB

• The fifth transmembrane segment of the neuromedin B receptor is critical for high affinity neuromedin B binding [16].
• Therefore, the data suggest that NB receptor pathways are importantly involved in thyrotroph gene regulation and function, leading to a state where TSH release is facilitated especially in response to TRH, but probably with a less-bioactive TSH [27].
• Insulinomas were characterised by a very high incidence of GLP-1, CCK(2) and VPAC(1) receptors, with the GLP-1 receptors expressed in a particularly high density; they expressed sst(2) in two-thirds and sst(1) in approximately half of the cases and lacked CCK(1) and NMB receptors [28].
• Based on its map position and the putative function of the encoded peptide, NMB can be considered as a candidate gene both for BBS4 and the development of human obesity [29].
• We examined the effect of two des-Met-bombesin analogues, [(CH3)2CHCO-His-Trp-Ala-Val-D-Ala-His-Leu-NHCH3] (ICI 216140) and [D-Phe6,des-Met14]bombesin(6-14) ethylamide (DPDM-bombesin ethylamide), on neuromedin B-induced Ca2+ and [3H]arachidonate release in BALB 3T3 cells transfected with human neuromedin B receptors [30].

Analytical, diagnostic and therapeutic context of NMB

• By immunohistochemistry, both NMB and NMB-R were expressed in normal and cancerous colonic epithelial tissues [1].
• PD 168368 should prove useful for delineating the biological role of NMB and selectively blocking NMB signaling in bioassays and as a lead for the development of more selective nonpeptide antagonists for the NMB receptor [31].
• In situ hybridization studies performed with cRNA probes specific for NMB or GRP mRNA show that the distribution of cells expressing either mRNA in brain is very distinct [32].
• Molecular cloning of cDNAs encoding the human bombesin-like peptide neuromedin B. Chromosomal localization and comparison to cDNAs encoding its amphibian homolog ranatensin [20].
• Using gel filtration and high pressure liquid chromatography techniques, the main peak of immunoreactive NMB coeluted with synthetic NMB [11].

References