Sequence 440 (siCTNNB1.2)

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Sequence siCTNNB1.2
Target CTNNB1 (Homo sapiens)
Description Catenin (cadherin-associated protein), beta 1, 88kDa

Ensembl: ENSG00000168036 UniGene: Hs.476018 EntrezGene: 1499 Ensembl Chr3: 41216000 - 41256938 Strand: 1 GO terms: 0000122 0000904 0001501 0001569 0001706 0001708 0001709 0001711 0001837 0003682 0003690 0003700 0003713 0004871 0005198 0005624 0005634 0005667 0005737 0005856 0005886 0005916 0007268

Design siRNA
Chemistry RNA
Sequence siRNA sense (21b) GGGTAGGGTAAATCAGTAATT / siRNA antisense (21b) TTACTGATTTACCCTACCCAT
Application gene silencing
Name siCTNNB1.2

References

Multiplexing siRNAs to compress RNAi-based screen size in human cells. Martin SE, Jones TL, Thomas CL, Lorenzi PL, Nguyen DA, Runfola T, Gunsior M, Weinstein JN, Goldsmith PK, Lader E, Huppi K, Caplen NJ. Nucleic Acids Res. 2007;35(8):e57.

Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM. J Child Neurol. 2016 Jun;31(7):899-906. PubMed:26823478

Comments

Background

Description. Beta-catenin is an adherens junction protein. Adherens junctions (AJs; also called the zonula adherens) are critical for the establishment and maintenance of epithelial layers, such as those lining organ surfaces. AJs mediate adhesion between cells, communicate a signal that neighboring cells are present, and anchor the actin cytoskeleton. In serving these roles, AJs regulate normal cell growth and behavior. At several stages of embryogenesis, wound healing, and tumor cell metastasis, cells form and leave epithelia. This process, which involves the disruption and reestablishment of epithelial cell-cell contacts, may be regulated by the disassembly and assembly of AJs. AJs may also function in the transmission of the 'contact inhibition' signal, which instructs cells to stop dividing once an epithelial sheet is complete (summary by Peifer, 1993). Gene Function. Work by Korinek et al. (1997) and by Morin et al. (1997) established that the APC gene (611731), which is mutant in adenomatous polyposis of the colon, is a negative regulator of beta-catenin signaling. The APC protein normally binds to beta-catenin, which interacts with Tcf and Lef transcription factors. Korinek et al. (1997) cloned a gene, which they called hTcf-4, that is a Tcf family member expressed in colonic epithelium. The protein product (Tcf4) transactivates transcription only when associated with beta-catenin. Nuclei of APC -/- colon carcinoma cells were found to contain a stable beta-catenin/Tcf4 complex that was constitutively active, as measured by transcription of a Tcf reporter gene. Reintroduction of APC removed beta-catenin from Tcf4 and abrogated the transcriptional activation. Korinek et al. (1997) concluded that constitutive transcription of Tcf target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium. Morin et al. (1997) likewise found that the protein products of mutant APC genes present in colorectal tumors were defective in downregulating transcriptional activation mediated by beta-catenin and T-cell transcription factor-4 (TCF4), now known as transcription factor-7-like-2 (TCF7L2; 602228). Furthermore, colorectal tumors with intact APC genes were found to contain activating mutations of beta-catenin that altered functionally significant phosphorylation sites. These results indicated that regulation of beta-catenin is critical to the tumor suppressive effect of APC and that this regulation can be circumvented by mutations in either APC or beta-catenin.

Roose et al. (1999) demonstrated in mice that one of the targets of the beta-catenin/TCF7L2 interactions in epithelial cells is TCF7 (189908). Roose et al. (1999) suggested that TCF7 may act as a feedback repressor of beta-catenin/TCF7L2 target genes, and thus may cooperate with APC to suppress malignant transformation of epithelial cells.

Rodova et al. (2002) presented evidence for beta-catenin-induced expression of PKD1 (601313). They analyzed the promoter region of PKD1 and identified numerous transactivating factors, including 4 TCF-binding elements (TBEs). Beta-catenin induced a reporter construct containing TBE1 6-fold when cotransfected into HEK293T cells, which express TCF4 (TCF7L2). Dominant-negative TCF4 or deletion of the TBE1 sequence inhibited the induction. Gel shift assays confirmed that TCF4 and beta-catenin could complex with the TBE1 site, and HeLa cells stably transfected with beta-catenin responded with elevated levels of endogenous PKD1 mRNA. Rodova et al. (2002) concluded that the PKD1 gene is a target of the beta-catenin/TCF pathway.

Van de Wetering et al. (2002) showed that disruption of beta-catenin/TCF4 activity in colorectal cancer cells induced a rapid G1 arrest and blocked a genetic program that was physiologically active in the proliferative compartment of colon crypts. Coincidently, an intestinal differentiation program was induced. The TCF4 target gene MYC (190080) played a central role in this switch by direct repression of the CDKN1A (116899) promoter. Following disruption of beta-catenin/TCF4 activity, the decreased expression of MYC released CDKN1A transcription, which in turn mediated G1 arrest and differentiation. The authors concluded that the beta-catenin/TCF4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells.

Glucuronic acid epimerase (GLCE; 612134) is responsible for epimerization of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA) of the cell surface polysaccharide heparan sulfate (HS), endowing the nascent HS polysaccharide chain with the ability to bind growth factors and cytokines. Using stepwise deletion and site-directed mutagenesis, Ghiselli and Agrawal (2005) identified 2 cis-acting binding elements for the beta-catenin-TCF4 complex in the enhancer region of the GLCE promoter. Electrophoretic mobility shift and supershift analyses confirmed binding of beta-catenin-TCF4 to these sequences of GLCE. GLCE expression in human colon carcinoma cell lines correlated with the degree of activation of the beta-catenin-TCF4 transactivation complex. Furthermore, ectopic expression of beta-catenin-TCF4 increased the GLCE transcript level and enhanced the rate of GlcA epimerization in HS. Ghiselli and Agrawal (2005) concluded that the beta-catenin-TCF4 transactivation pathway plays a major role in modulating GLCE expression, thus contributing to regulation of HS biosynthesis and its structural organization.

Animal Model. An effector of intercellular adhesion, beta-catenin also functions in Wnt signaling, associating with Lef1/Tcf DNA-binding proteins to form a transcription factor. Gat et al. (1998) reported that this pathway also operates in keratinocytes and that mice expressing beta-catenin controlled by an epidermal promoter undergo a process resembling de novo hair morphogenesis. The new follicles form sebaceous glands and dermal papilla, normally established only in embryogenesis. As in embryologically initiated hair germs, transgenic follicles induce Lef1, but follicles are disoriented and defective in Sonic hedgehog polarization. Additionally, proliferation continues unchecked, resulting in 2 types of tumors (epithelioid cysts and trichofolliculomas) that are also found in humans. Older transgenic mice develop pilomatricomas. These findings suggested that transient beta-catenin stabilization may be a key player in the epidermal signal leading to hair development and implicated aberrant beta-catenin activation in hair tumors.

Harada et al. (1999) found that targeted deletion of exon 3 in mice, which encodes serines and threonines phosphorylated by GSK3-beta, caused adenomatous intestinal polyps resembling those in Apc knockout mice. Some nascent microadenomas were also found in the colon.

To study the role of beta-catenin in skin development, Huelsken et al. (2001) introduced a conditional mutation of the gene in the epidermis and hair follicles of mice using Cre/loxP technology. When beta-catenin was mutated during embryogenesis, formation of placodes that generate hair follicles was blocked. The authors showed that beta-catenin is required genetically downstream of Tabby (300450) and downless (EDAR; 604095) and upstream of bone morphogenetic proteins (see 112262) and Shh (600725) in placode formation. If beta-catenin was deleted after hair follicles had formed, hair was completely lost after the first hair cycle. Further analysis demonstrated that beta-catenin is essential for fate decisions of skin stem cells: in the absence of beta-catenin, stem cells failed to differentiate into follicular keratinocytes and instead adopted an epidermal fate.

Saadi-Kheddouci et al. (2001) found that transgenic mice that overproduced an oncogenic form of beta-catenin in the epithelial cells of the kidney developed severe polycystic lesions soon after birth.

To examine whether activating beta-catenin signaling could regulate mammalian brain development, Chenn and Walsh (2002) developed transgenic mice overexpressing an amino-terminal truncated form of beta-catenin fused at the carboxyl-terminal with green fluorescent protein in neuroepithelial precursors. The mice developed enlarged brains with increased cerebral cortical surface area and folds resembling sulci and gyri of higher mammals. Brains from transgenic animals have enlarged lateral ventricles lined with neuroepithelial precursor cells, reflecting an expansion of the precursor population. Compared with wildtype precursors, a greater proportion of transgenic precursors reenter the cell cycle after mitosis. Chenn and Walsh (2002) concluded that their results showed that beta-catenin can function in the decision of precursors to proliferate or differentiate during mammalian neuronal development and suggested that beta-catenin can regulate cerebral cortical size by controlling the generation of neuronal precursor cells.

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