Disease relevance of Wdr5

• METHODS: Big Blue transgenic male mice (C57Bl/6) were inoculated with H. pylori (strain SS1) or Helicobacter felis (strain CS1) for 6 and 12 months [1].
• The incidence of MNU-induced lymphomas was 84% in Big Blue lacI mice compared to 14% in MGMT+Big Blue lacI mice [2].
• The animals were killed 16 weeks after operation or injection, the entire esophageal mucosa was harvested, and mutation frequency was determined through standard Big Blue Mutagenesis Assay. RESULTS: Gross esophagitis was evident in all operated animals [3].
• The Big Blue transgenic B6C3F1 mouse carries multiple copies of bacteriophage lambda, each with a lacI mutational target gene, integrated into mouse chromosome 4 [4].
• Herein, we present the first analysis of mutation frequency and pattern in thymic tumors from a mouse model of Li-Fraumeni syndrome (p53+/- murine model) using the Big Blue assay with sequencing of all mutants [5].

Psychiatry related information on Wdr5

• No changes in locomotor activity and no signs of anxiolytic-like behavior were produced by dynorphins A and B. Big Dyn (2.5 nmol) increased time spent in the open branches of the elevated plus maze apparatus with no changes in general locomotion [6].

High impact information on Wdr5

• Overproduction of Tob represses BMP2-induced, Smad-mediated transcriptional activation [7].
• Finally, BMP-2-induced bone formation on adult mouse calvariae in vivo was enhanced by CIZ deficiency [8].
• To determine whether osteoblast differentiation is impaired, we used primary osteoblasts isolated from the transgenic mice and showed that BMP signaling is blocked and BMP2-induced mineralized bone matrix formation was inhibited [9].
• BMP-2-induced ALP activity could be rescued by transfection of wild-type (wt) BMPR-IB into 2T3 clones containing trBMPR-IB [10].
• BMP-2 induced 2T3 cells to differentiate into mature osteoblasts or adipocytes depending upon culture conditions [10].

Chemical compound and disease context of Wdr5

• When Big Blue(trade mark) mice were treated with MMS (160 mg/kg) or ENU (125 or 250 mg/kg) and the phages rescued from mature sperm were infected to the strains, the mutation frequency (MF) of phages from ENU-treated mice at a dose of 250 mg/kg in strain YG5152 was about two times higher than that in strain SCS-8 [11].
• Evaluation of the genetic toxicity of the peroxisome proliferator and carcinogen methyl clofenapate, including assays using Muta Mouse and Big Blue transgenic mice [12].
• METHODS: Big Blue mouse embryonic fibroblasts, which carry a lambda phage cII transgene, were treated with acrylamide [13].

Biological context of Wdr5

• Wdr5, a WD-40 protein, regulates osteoblast differentiation during embryonic bone development [14].
• These results indicate that Cdk6 is a critical regulator of BMP-2-induced osteoblast differentiation and that its Smads-mediated down-regulation is essential for efficient osteoblast differentiation [15].
• To determine whether oxidative stress after cerebral ischemia-reperfusion affects genetic stability in the brain, we studied mutagenesis after forebrain ischemia-reperfusion in Big Blue transgenic mice (male C57BL/6 strain) containing a reporter lacI gene, which allows detection of mutation frequency [16].
• Associated with this inhibitory effect of Go6976, BMP-2 induced a selective and a dose-dependent Ser916 phosphorylation/activation of PKD, which was also blocked by Go6976 [17].
• Here, we examined the involvement of Cas-interacting zinc finger protein (CIZ) in the modulation of BMP2-induced osteoblastic cell differentiation [18].

Anatomical context of Wdr5

• Overall, our findings suggest that Wdr5 accelerates osteoblast differentiation in association with activation of the canonical Wnt pathway [14].
• Using differential display polymerase chain reaction, we have identified a novel gene, named BIG-3 (BMP-2-induced gene 3 kb), that is induced as a murine prechondroblastic cell line, MLB13MYC clone 17, acquires osteoblastic features in response to BMP-2 treatment [19].
• We investigated the effects of single and combined exposures to two ubiquitous environmental carcinogens, polycyclic aromatic hydrocarbons and UVA radiation, in Big Blue mouse embryonic fibroblasts [20].
• To this end, a study was conducted to determine the Mfs and spectrum of mutations induced at these loci in splenic T cells from male B6C3F1 Big Blue mice (6 weeks old) exposed to N-ethyl-N-nitrosourea (ENU) [21].
• Treatment of the E15 or the P1 SCG with BMP-2 induced expression of trkC mRNA and responsiveness of sympathetic neurons to NT3 as measured by neurite outgrowth [22].

Associations of Wdr5 with chemical compounds

• In sharp contrast, 17beta-estradiol (E(2)) suppressed BMP-2-induced osteoblast progenitor commitment and differentiation [23].
• We studied the mutagenicity of the proximate bladder carcinogen, N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) in embryonic fibroblasts of the Big Blue mouse [24].
• BMP-2 induced COX-2 mRNA and prostaglandin (PG) production in cultured osteoblasts [25].
• The role of p38 and JNK in mediating BMP-2-induced stimulation of osteoblastic cell differentiation was evaluated using the respective specific inhibitors SB203580 and SP600125 [26].
• Oxazepam is mutagenic in vivo in Big Blue transgenic mice [27].

Physical interactions of Wdr5

• These results strongly suggest that both the Hox- and the Smad-binding regions play a role in BMP-2-induced activation of the OPN promoter [28].

Regulatory relationships of Wdr5

• The enforced expression of Cdk6 blocked BMP-2-induced osteoblast differentiation to various degrees, depending on the level of its overexpression [15].
• Over-expression of Wnt3a blocked BMP-2-induced inhibition of myotube formation in C2C12 cells when switched to low mitogen medium [29].
• Specific inhibitors for p38 kinase inhibited BMP2-induced adipocytic differentiation and transcriptional activation of PPARgamma, whereas overexpression of Smad6 had no effect on transcriptional activity of PPARgamma [30].
• Expression of dominant-negative PI 3-kinase or dominant-negative Akt inhibited BMP-2-induced BMP-2 transcription [31].
• These data show that SKIP has specific inhibitory effects on BMP-2-induced differentiation and implicate SKIP to be a novel regulator of the differentiation programming induced by TGF-beta signals [32].

Other interactions of Wdr5

• Moreover, TGF-beta 1 opposed BMP-2-induced osteogenic transdifferentiation through Dlx5 suppression by de novo induction of AP-1 [33].
• Furthermore, our data also suggest that functional Notch signaling is essential not only for BMP2-induced osteoblast differentiation but also for BMP signaling itself [34].
• These results indicate that Erk is involved in BMP-2 induced osteoblast differentiation [35].
• BMP-2 induced transcription of Dlx3 within 12 h of treatment of keratinocytes cultured in vitro [36].
• Interestingly, this ectopic expression of Smad6 blocks BMP2-induced TAK1 activation and p38 phosphorylation [37].

Analytical, diagnostic and therapeutic context of Wdr5

• In addition, intraarticular injections of BMP-2 induced chondrophytes [38].
• Real-time quantitative RT-PCR analysis was used to validate BMP2-induced gene expression patterns in C2C12 cells [39].
• Our studies were designed to determine whether the Big Blue system could be used to detect differences in the in vivo mutagenic activity between the carcinogen/non-carcinogen pair 2,4- and 2,6-DAT and to determine whether the in vivo mutagenesis assay results correspond to the rodent carcinogen bioassay results [4].
• In this study, the DNA sequence spectra of lacI mutations observed in the liver of B[a]P-treated Big Blue mice at hepatectomy and at time of sacrifice were compared with each other and with the spectrum of spontaneous liver mutations [40].
• Whereas dynorphins A and B (i.c.v., 0.05 and 7 nmol/animal, respectively) produced analgesia in the hot-plate test Big Dyn did not [6].

References