LBH (gene)
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The LBH (Limb Bud-Heart) gene is a highly conserved human gene that produces the LBH protein,[5] a transcription co-factor in the Wnt/β-catenin pathway.[6] Upon transcriptional activation of β-catenin, LBH goes on to act as a regulator of cell proliferation and differentiation through multiple transcriptional targets.[7][8] The gene is located on the p arm of chromosome 2 and is roughly 28 kb long.[5] Current ongoing studies are examining its role in developmental and oncological settings.
Located on chromosome 2, the full sequence is 28495 base pairs long. It contains three exons that will be translated to create the final protein product. Currently, there is no identified promoter region. LBH has a high degree of similarity among many vertebrate species.[5] This is most likely evident of its importance in development and stem cell regulation. Interestingly, LBH has no known paralogs, despite its multifunctionality and expression in different tissues at various stages of development.[5]
Protein
The LBH or Limb-Bud and Heart protein is 105 aa long nuclear protein and is highly conserved across vertebrate species.[5] LBH is a disordered, acidic protein. It lacks any globular fold or secondary and tertiary structures, placing it in the class of intrinsically disordered proteins (IDPs).[9] Research is ongoing on how LBHs conformational flexibility affects its role as a transcriptional regulator. IDPs are known to undergo disorder to order transitions in the presence of certain binding partners.[10] Due to LBHs disordered structure, it may experience multi-functionality through the binding to different targets, producing different transcriptional effects.
Mechanism
LBH or Limb-Bud-Heart was first identified in a 2001 study on transcriptional cofactors for limb patterning in mice. LBH was noted for its expression in developing limb buds and heart formation, hence its name. LBH was hypothesized to act as a transcriptional cofactor due to preliminary examinations of its protein structure and composition.[7] LBH was then found to be directly downstream of the canonical Wnt/β-catenin pathway by downregulating the expression of Wnt, preventing signal completion.[7] The Wnt/β-catenin pathway is a highly conserved pathway that is expressed in a variety of tissues and stages.[11] Direct overlap of in vivo expression of Wnt/β-catenin pathway activation and LBH expression during limb bud development gives evidence for a direct interaction between Wnt/β-catenin and LBH.[7]
Recent studies have found that LBH has a significant role in the regulation of stem cell growth and proliferation in mammary glands. LBH induces expression of ΔNp63, a key epithelial stem cell transcription factor, to promote basal MaSC differentiation and proliferation growing the basal mammary gland. This is compared to luminal expansion and differentiation, increasing the movement and differentiation of the basal MaSC cells to the luminal surface. Knockdowns in mice have resulted in reduced mammary gland growth during puberty and pregnancy.[8] Inversely, overexpression has been noted in basal subtype breast cancers, furthering LBHs effect on stem cell regulation.[7]