Disease relevance of Bhlhb4

• Electroretinograms (ERGs) in the adult Bhlhb4 knockout (Bhlhb4(-/-)) showed that the loss of Bhlhb4 resulted in disrupted rod signaling and profound retinal dysfunction resembling human congenital stationary night blindness (CSNB), characterized by the loss of the scotopic ERG b-wave [1].
• These results indicate that beta 4 integrin promotes tumor progression by amplifying ErbB2 signaling and identify beta 4 as a potential target for molecular therapy of breast cancer [2].
• Using recombinant protein kinase C adenoviruses, overexpression of protein kinase Cdelta but not protein kinase Calpha in primary keratinocytes increased beta4 serine phosphorylation, decreased alpha6beta4 localization to the hemidesmosome complexes, and reduced keratinocyte attachment [3].
• The clustered neuronal nAchRs subunit genes, alpha 3 and beta 4, are expressed in amacrine and ganglion cells where they are used to assemble functional receptor subtypes [4].
• Targeted expression of alpha6beta4 in the suprabasal layers of transgenic mouse epidermis dramatically increased the frequency of papillomas, carcinomas and metastases induced by chemical carcinogenesis, independent of the beta4 cytoplasmic domain [5].

High impact information on Bhlhb4

• Ex vivo studies indicate that beta 4 forms a complex with ErbB2 and enhances activation of the transcription factors STAT3 and c-Jun [2].
• To study the contribution of the integrin alpha 6 beta 4 in hemidesmosome formation and their anchoring properties, we inactivated the beta 4 gene in mice by targeted gene disruption [6].
• These cells expressed the V alpha 8-J alpha TA72, V beta 4 heterodimer in both progressive infection and protective immunity and across several major histocompatibility haplotypes [7].
• Recombinant LACK antigen from L. major induced comparable IL-4 production in V beta 4 V alpha 8 CD4+ cells [8].
• Thus, the IL-4 required for Th2 development and susceptibility to L. major is produced by a restricted population of V beta 4 V alpha 8 CD4+ T cells after cognate interaction with a single antigen from this complex organism [8].

Biological context of Bhlhb4

• In the pancreas, Bhlhb4 is expressed in a transient fashion that suggests a role in the pancreatic endocrine cell lineage [9].
• Fluorescence in situ hybridization (FISH) and genetic mapping place Bhlhb4 at the telomeric end of mouse chromosome 2 (H3-H4), syntenic to human chromosome 20q13 [9].
• Notably, a critical beta4 subunit function is to preclude BK channels from contributing to membrane repolarization and thereby broaden action potentials [10].
• Thus, beta4 may be the endogenous open-channel blocker responsible for resurgent kinetics [11].
• Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival [12].

Anatomical context of Bhlhb4

• Here we demonstrate that the burst of IL-4 mRNA, peaking in draining lymph nodes of BALB/c mice 16 hr after infection, occurs within CD4+ T cells that express V beta 4 V alpha 8 T cell receptors [8].
• Consistent with breakdown of the dentate filter, beta4 knockouts show distinctive seizures emanating from the temporal cortex, demonstrating a unique nonsynaptic mechanism for gate control of hippocampal synchronization leading to temporal lobe epilepsy [10].
• In Purkinje cells, the only known sodium channel-associated subunit that has a cytoplasmic sequence with several positive charges and clustered hydrophobic/aromatic residues is beta4 (KKLITFILKKTREK; beta4(154-167)) [11].
• The conclusion that "thymosin" beta 4 does not originate solely in the thymus gland is supported by the high concentrations found in tissues of athymic (nu/nu) mice [13].
• Antisera that recognize the alpha 6 and beta 4 subunits of integrins were found by immunoelectron microscopy to localize to hemidesmosomes in the basal cells of mouse corneal epithelium [14].

Associations of Bhlhb4 with chemical compounds

• Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis [2].
• Another population (type B) of cells with large soma did not contain alpha3 and beta4 mRNAs but, systematically, alpha6 and beta3 (and often alpha4) and responded to nicotinic agonists in the order of nicotine > cytisine [15].
• The alpha6beta4 integrin-a laminin-5 receptor-mediates assembly of hemidesmosomes and recruitment of Shc and phosphoinositide 3-kinase through the unique cytoplasmic extension of beta4 [16].
• Type 3 nAChRs bind epibatidine with high affinity in equilibrium binding experiments and show that cytisine is as effective as nicotine in electrophysiological experiments; their distribution and persistence in beta2 -/- mice strongly suggest a subunit composition of alpha3 beta4 [17].
• In mammals, beta4-GT has been recruited for a second biosynthetic function, the production of lactose which occurs exclusively in the lactating mammary gland [18].

Physical interactions of Bhlhb4

• Interestingly, the Sp- and Sox10-binding sites on the beta4 promoter are located immediately adjacent to each other, raising the possibility that the two sets of factors functionally interact to regulate receptor gene expression [19].

Enzymatic interactions of Bhlhb4

• Enhanced expression of Ca2+ channel alpha1A and beta4 subunits and phosphorylated tyrosine hydroxylase in the adrenal gland of N-type Ca2+ channel alpha1B subunit-deficient mice with a CBA/JN genetic background [20].
• The mouse mutant lethargic (lh) exhibits severe neurological defects due to a mutation that deletes the alpha1 subunit interaction domain of the beta4 subunit [21].

Regulatory relationships of Bhlhb4

• Cell culture studies showed that astrocyte expression of the beta4 and alpha5 integrins was significantly upregulated by IL-6 and IFN-alpha, respectively, while endothelial expression of these integrins was unchanged [22].
• Expression of the beta 4 integrin subunit induces monocytic differentiation of 32D/v-Abl cells [23].
• These findings provide evidence that beta4 signaling promotes epidermal growth and wound healing through a previously unrecognized effect on nuclear translocation of NF-kappaB and mitogen-activated protein kinases [16].
• In this report, we demonstrate that neither full-length nor truncated beta4 protein is expressed in lh/lh mice [24].
• We conclude that several properties of alpha1A and alpha1B proteins are not uniquely regulated by beta4 in vivo and may be rescued by beta1-3 subunit reshuffling [21].

Other interactions of Bhlhb4

• We find that RAR beta 1/beta 3 promoter activity, which is apparently confined to the embryonic CNS, is not modified by RA treatment, unlike that of the RAR beta 2/beta 4 promoter (Mendelsohn et al., 1991) [25].
• Two reports in this issue of Neuron reveal two transcription factors (Foxn4 and Bhlhb4) that contribute to the development of this remarkable cellular diversity [26].
• Keratinocytes from beta4 mutant mice undergo extensive spreading but fail to proliferate and migrate in response to epidermal growth factor (EGF) on laminin-5 [16].
• We have generated a conditional knockout mouse strain, in which the gene encoding the beta4 integrin subunit (Itgb4) was inactivated only in small stretches of the skin [27].
• Since beta subunits regulate critical alpha1 subunit properties in heterologous expression systems, loss of beta4 in lethargic could dramatically alter channel localization and behavior unless beta1-3 subunits can be used as substitutes in vivo [21].

Analytical, diagnostic and therapeutic context of Bhlhb4

• Sites of beta 4 expression in mice were detected by autoradiographic analysis of tissues collected from mice 24 or 48 h after intravenous injection of 125I-labeled mAb 346-11A [28].
• BPA and antibodies to alpha 6 and beta 4 were used for immunofluorescence microscopy on frozen sections of intact corneas healing in vivo 1-18 h [29].
• PCR products representing subunit gene expression were strongly and consistently amplified for alpha1C, alpha1D, alpha1E, alpha2delta, beta1, beta3, and beta4 but not for alph1A, alpha1B, alpha1S, beta2, or gamma [30].
• To examine this question in detail, expression of the nicotine acetylcholine receptor (nAChR) subunits alpha3, alpha4, alpha5, alpha7, beta2, and beta4 was measured in the dorsal hippocampus using immunohistochemistry in mouse strains or lines BALB/c, C3H/J, C57BL/6, CBA/J, DBA/2, Long Sleep (LS), Short Sleep (SS), and CF1 [31].
• Molecular cloning and expression of mouse mg(2+)-dependent protein phosphatase beta-4 (type 2C beta-4) [32].

References