Monday, August 1, 2011

Taller Height by inhibiting Cadherin's?

Cadherin 13 is upregulated 3.1 fold by LSJL.  Some sources state that CDH13 affects Ca2+ mobilization and cell migration which could relate to a height increase effect.

Cadherin 13 in cancer.

"Cadherin 13 (CDH13, T-cadherin, H-cadherin) is an atypical member of the cadherin family, devoid of a transmembrane domain and anchored to the exterior surface of the plasma membrane via a glycosylphosphatidylinositol anchor. CDH13 [affects] cellular behavior largely through its signaling properties. It is often down-regulated in cancerous cells[meaning CDH13 is likely catabolic]. CDH13 re-expression in most cancer cell lines inhibits cell proliferation and invasiveness, increases susceptibility to apoptosis, and reduces tumor growth in in vivo models. CDH13 is up-regulated in blood vessels growing through tumors and promotes tumor neovascularization[maybe CDH13 can promote growth plate vasularization].  CDH13 overexpression in endothelial cells promotes their proliferation and migration, and has a pro-survival effect[CDH13 may be anabolic possibly for stem or cartilage cells]."

"Intracellular domains of classical cadherins are associated with α- and β-catenins, which affect the dynamics of the actin-based cytoskeleton"

"CDH13 [may] act as a putative receptor for high molecular weight adiponectin, a cytokine produced by adipocytes"

"CDH13 is able to form homophilic dimers by a noncanonical mechanism, and is a receptor for low density lipoprotein (LDL) and high molecular weight (HMW) adiponectin. CDH13 can form complexes with CDH13 fragments present in the substratum, which promotes endothelial cell motility. CDH13 interacts with transmembrane proteins (GRP78, β3 integrin) and signals to Akt. Integrin-linked kinase (ILK) is also involved in CDH13 signaling. CDH13 might also interact with transmembrane receptors, such as receptor tyrosine kinases (RTK) or G protein-coupled receptors (GPCR)"

CDH13 is downregulated in osteosarcoma but no cancers involving chondrogenic cells.

"Dnmt3a may be involved in CDH13 promoter methylation. Dnmt3b is associated with CDH13 promoter and represses it irrespectively of its methyltransferase activity"

"CDH13 down-regulation results in increased epidermal growth factor receptor (EGFR) phosphorylation, β1 integrin internalization due to stimulation of endocytosis, and loss of intercellular CDH13 dimers. G2 to M phase transition is also stimulated by a p21CIP1/WAF1-dependent mechanism."

"CDH13 up-regulation promotes survival and proliferation via activation of Akt, which leads to
inhibition of GSK3β, reduced degradation of β-catenin, resulting in its accumulation in the nucleus and increased production of cyclin D1 and stimulation of G1 to S-phase transition; activation of mTOR, which stimulates proliferation (via activation of p70S6K kinase);
inhibition of proapoptotic signaling (p38 MAP kinase and caspase-3)."

Methylation of cyclin-dependent kinase inhibitors, XAF1, JUNB, CDH13 and soluble Wnt inhibitors in essential thrombocythaemia. states that CDH13 is a cyclin-dependent kinase inhibitor.

This study states that Cadherin 13 may play a role in adult height:

Linkage analysis of adult height in a large pedigree from a Dutch genetically isolated population.

"The pedigree was derived from a young genetically isolated Dutch population, where genetic heterogeneity is expected to be low and linkage disequilibrium has been shown to be increased. Complex segregation analysis confirmed high heritability of adult height, and suggested mixed model of height inheritance in this population. Three genome-wide significant and additionally at least four suggestive loci [are] involved in height. Significant peaks were located at the chromosomal regions 1p32, 2p16 and 16q24. For the latter region, a strong association signal (FDR q < 0.05) was obtained for 19 SNPs, 17 of them were located in the CDH13 (cadherin 13) gene of which one (rs1035569) explained 1.5% of the total height variance."

"A locus involved in human height [is] JAZF1"

Genes mentioned in study that could possibly be used to manipulate for height growth: COL9A2 and EIF2AK3.

"[CDH13] protein is a calcium dependent cell–cell adhesion glycoprotein comprised of five extracellular cadherin repeats, a transmembrane region but, unlike the typical cadherin superfamily member, lacks the highly conserved cytoplasmic region"

Possible theories on CDH13 and height: "Despite the fact that CDH13 was not described earlier as a candidate gene for human stature, cell proliferation and cell–cell adhesion may play a role in regulation of adult height. Mechanism of such effect may be based on involvement of cadherins in bone metabolism: cadherin-mediated cell–cell adhesion is essential for the commitment of cells to osteoblastic differentiation. Disturbance of differentiation of mesenchymal precursors into osteogenic, myogenic, or adipogenic pathways may explain the association between CDH13 and ossification of the posterior longitudinal ligament of the spine or the level of adiponectin having a variety of metabolic effects on obesity, insulin sensitivity and atherosclerosis"

LSJL also upregulates Cdh10 and Cdh18 and downregulates Cdh15 and Cdh11.

MicroRNA-375, a new regulator of cadherin-7, suppresses the migration of chondrogenic progenitors.

"The expression of miR-375 decreased upon chondrogenic differentiation of limb mesenchymal cells. Blockade of miR-375 via peptide nucleic acid (PNA)-based antisense oligonucleotides (ASOs) increased the migration of chondrogenic progenitors, the formation of precartilage condensations and the expression level of cadherin-7. miR-375 was necessary and sufficient to down-regulate cell migration through negative regulation of cadherin-7 by the direct interaction with 3' UTR of cadherin-7. miR-375 is also involved in the cell migration and precartilage condensation mediated by p38MAPK, a positive signaling in the chondrogenic differentiation.  miR-375 negatively modulates cell migration and subsequent precartilage condensation by targeting cadherin-7."

Conversely, Cadherin 7 may be a beneficial gene for height growth.

"Mesenchymal condensation results from either increased mitotic activity or from increased cell movement and subsequent mesenchymal cell packing density without increased cell proliferation"

"Cadherin-7-mediated cell migration is modulated by p38 MAPK"

"During active migration, cells continue to maintain cell–cell contacts regulated by N-cadherins and the gap junction protein, Cx43"

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