Maximal Activity of the Luteinizing Hormoneβ-Subunit Gene Requires β-Catenin

2007 ◽  
Vol 21 (4) ◽  
pp. 963-971 ◽  
Author(s):  
Travis B. Salisbury ◽  
April K. Binder ◽  
Jean C. Grammer ◽  
John H. Nilson
Keyword(s):  
Regulatory Region ◽  
Wnt Signaling Pathway ◽  
Maximal Activity ◽  
Early Gene ◽  
Orphan Nuclear Receptor ◽  
Functional Interaction ◽  
Reporter Assays ◽  
Transcriptional Complex ◽  
Canonical Wnt ◽  
Interfering Rna

Abstract GnRH regulates expression of LHB via transcriptional regulation of early growth response 1 (EGR1), an immediate early gene that encodes a zinc-finger DNA-binding protein. EGR1 interacts functionally with the orphan nuclear receptor steroidogenic factor 1 (SF1) and pituitary homeobox 1, a member of the paired-like homeodomain family. The functional synergism of this tripartite interaction defines the maximal level of LHB transcription that can occur in response to GnRH. Results presented herein provide new evidence that the interaction between SF1 and EGR1 also requires β-catenin, a transcriptional coactivator and member of the canonical Wnt signaling pathway. For instance, targeted reduction of β-catenin attenuates activity of a GnRH-primed LHB promoter. Additional gene reporter assays indicate that overexpression of β-catenin, or its targeted reduction by small interfering RNA, modulates activity of both SF1 and EGR1 as well as their functional interaction. β-Catenin coimmunoprecipitates with SF1. Moreover, an SF1 mutant that lacks a β-catenin binding domain has compromised transcriptional activity and fails to interact synergistically with EGR1. Finally, GnRH promotes β-catenin colocalization with SF1 and EGR1 on the endogenous mouse Lhb promoter-regulatory region. Taken together, these data suggest that β-catenin binds to SF1 and that this interaction is required for subsequent functional interaction with EGR1. Thus, these data identify β-catenin as a new and required member of the basal transcriptional complex that allows the LHB promoter to achieve maximal activity in response to GnRH.

P1615HECT-Type Ubiquitin E3 Ligase ITCH attenuates cardiac hypertrophy by suppressing Wnt signaling pathway

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Goto ◽  
Y Otaki ◽  
T Watanabe ◽  
T Aono ◽  
K Watanabe ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
E3 Ligase ◽  
Pressure Overload ◽  
Aortic Constriction ◽  
Ubiquitin E3 Ligase ◽  
Ubiquitin Proteasome ◽  
Canonical Wnt ◽  
Interfering Rna

Abstract Background The homologous to the E6-AP carboxyl terminus (HECT)–type ubiquitin E3 ligase ITCH is an enzyme that plays an important role in ubiquitin proteasomal protein degradation. Dishevelled proteins (Dvl1, Dvl2 and Dvl3), which are involved in canonical Wnt/β catenin signaling pathway, play a role in cardiac hypertrophy. Purpose The aim of this study was to examine whether ITCH interacts with Dvls and prevents cardiac hypertrophy induced by pressure overload. Methods and results We confirmed the protein interaction between ITCH and Dvls in cardiomyocytes. Overexpression of ITCH decreased protein expression levels of Dvls, phospho-GSK3β and β-catenin. Conversely, knockdown of ITCH using small interfering RNA augmented canonical Wnt/β catenin signaling pathway. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of ITCH (ITCH-Tg) and wild-type (WT) mice. The canonical Wnt/β catenin signaling pathway was inhibited and cardiac hypertrophy was attenuated in ITCH-Tg mice compared with WT mice after TAC. Overexpression of ITCH in cardiomyocytes Conclusion We demonstrated that ITCH targets Dvls for ubiquitin-proteasome degradation in cardiomyocytes and ameliorates cardiac hypertrophy by suppressing canonical Wnt/β catenin signaling pathway.

scholarly journals Welcoming β-Catenin to the Gonadotropin-Releasing Hormone Transcriptional Network in Gonadotropes

2008 ◽  
Vol 22 (6) ◽  
pp. 1295-1303 ◽  
Author(s):  
Travis B. Salisbury ◽  
April K. Binder ◽  
John H. Nilson
Keyword(s):  
Dna Binding ◽  
Binding Proteins ◽  
Wnt Signaling Pathway ◽  
Dna Binding Proteins ◽  
Transcriptional Network ◽  
Early Gene ◽  
Orphan Nuclear Receptor ◽  
Signature Genes ◽  
New Findings ◽  
Regulated Expression

Abstract GnRH binds its G-coupled protein receptor, GnRHR, on pituitary gonadotropes and stimulates transcription of Cga, Lhb, and Fshb. These three genes encode two heterodimeric glycoprotein hormones, LH and FSH, that act as gonadotropins by regulating gametogenesis and steroidogenesis in both the testes and ovary. GnRH also regulates transcription of Gnrhr. Thus, regulated expression of Cga, Lhb, Fshb, and Gnrhr provides a genomic signature unique to functional gonadotropes. Steadily increasing evidence now indicates that GnRH regulates transcription of its four signature genes indirectly through a hierarchical transcriptional network that includes distinct subclasses of DNA-binding proteins that comprise the immediate early gene (IEG) family. These IEGs, in turn, confer hormonal responsiveness to the four signature genes. Although the IEGs confer responsiveness to GnRH, they cannot act alone. Instead, additional DNA-binding proteins, including the orphan nuclear receptor steroidogenic factor 1, act permissively to allow the four signature genes to respond to GnRH-induced changes in IEG levels. Emerging new findings now indicate that β-catenin, a transcriptional coactivator and member of the canonical WNT signaling pathway, also plays an essential role in transducing the GnRH signal by interacting with multiple DNA-binding proteins in gonadotropes. Herein we propose that these interactions with β-catenin define a multicomponent transcriptional network required for regulated expression of the four signature genes of the gonadotrope, Cga, Lhb, Fshb, and Gnrhr.

scholarly journals Inhibition of the canonical Wnt signaling pathway by a β-catenin/CBP inhibitor prevents heart failure by ameliorating cardiac hypertrophy and fibrosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thanachai Methatham ◽  
Shota Tomida ◽  
Natsuka Kimura ◽  
Yasushi Imai ◽  
Kenichi Aizawa
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Left Ventricular ◽  
Cardiac Wall ◽  
Macrophage Marker ◽  
Glycolysis Pathway ◽  
Canonical Wnt ◽  
Macrophage Accumulation

AbstractIn heart failure (HF) caused by hypertension, the myocyte size increases, and the cardiac wall thickens. A low-molecular-weight compound called ICG001 impedes β-catenin-mediated gene transcription, thereby protecting both the heart and kidney. However, the HF-preventive mechanisms of ICG001 remain unclear. Hence, we investigated how ICG001 can prevent cardiac hypertrophy and fibrosis induced by transverse aortic constriction (TAC). Four weeks after TAC, ICG001 attenuated cardiac hypertrophy and fibrosis in the left ventricular wall. The TAC mice treated with ICG001 showed a decrease in the following: mRNA expression of brain natriuretic peptide (Bnp), Klf5, fibronectin, β-MHC, and β-catenin, number of cells expressing the macrophage marker CD68 shown in immunohistochemistry, and macrophage accumulation shown in flow cytometry. Moreover, ICG001 may mediate the substrates in the glycolysis pathway and the distinct alteration of oxidative stress during cardiac hypertrophy and HF. In conclusion, ICG001 is a potential drug that may prevent cardiac hypertrophy and fibrosis by regulating KLF5, immune activation, and the Wnt/β-catenin signaling pathway and inhibiting the inflammatory response involving macrophages.

Repeated CT elements bound by zinc finger proteins control the absolute and relative activities of the two principal human c-myc promoters

1993 ◽  
Vol 13 (9) ◽  
pp. 5710-5724
Author(s):  
E DesJardins ◽  
N Hay
Keyword(s):  
Zinc Finger ◽  
Tandem Repeats ◽  
Zinc Finger Protein ◽  
Consensus Sequence ◽  
Regulatory Region ◽  
Maximal Activity ◽  
Single Copy ◽  
Promoter Usage

Transcription of the human proto-oncogene c-myc is governed by two tandem principal promoters, termed P1 and P2. In general, the downstream promoter, P2, is predominant, which is in contrast to the promoter occlusion phenomenon usually observed in genes containing tandem promoters. A shift in human c-myc promoter usage has been observed in some tumor cells and in certain physiological conditions. However, the mechanisms that regulate promoter usage are not well understood. The present studies identify regulators which are required to promote transcription from both human c-myc promoters, P1 and P2, and have a role in determining their relative activities in vivo. A novel regulatory region located 101 bp upstream of P1 was characterized and contains five tandem repeats of the consensus sequence CCCTCCCC (CT element). The integrity of the region containing all five elements is required to promote transcription from P1 and for maximal activity from P2 in vivo. A single copy of this same element, designated CT-I2, also appears in an inverted orientation 53 bp upstream of the P2 transcription start site. This element has an inhibitory effect on P1 transcription and is required for P2 transcription. The transcription factor Sp1 was identified as the factor that binds specifically to the tandem CT elements upstream of P1 and to the CT-I2 element upstream of P2. In addition, the recently cloned zinc finger protein ZF87, or MAZ, was also able to bind these same elements in vitro. The five tandem CT elements can be functionally replaced by a heterologous enhancer that only in the absence of CT-I2 reverses the promoter usage, similar to what is observed in the translocated c-myc allele of Burkitt's lymphoma cells.

scholarly journals The Role of Canonical Wnt Signaling in Regulating Radioresistance

2018 ◽  
Vol 48 (2) ◽  
pp. 419-432 ◽  
Author(s):  
Yuanyuan Zhao ◽  
Leilei Tao ◽  
Jun Yi ◽  
Haizhu Song ◽  
Longbang Chen
Keyword(s):  
Wnt Signaling ◽  
Cancer Progression ◽  
Wnt Signaling Pathway ◽  
Growth Factor Receptor ◽  
Cancer Resistance ◽  
Canonical Wnt Signaling ◽  
Damage Repair ◽  
Epidermal Growth ◽  
Canonical Wnt

Radioresistance is a major obstacle in radiotherapy for cancer, and strategies are needed to overcome this problem. Currently, radiotherapy combined with targeted therapy such as inhibitors of phosphoinosotide 3-kinase/Akt and epidermal growth factor receptor signaling have become the focus of studies on radiosensitization. Apart from these two signaling pathways, which promote radioresistance, deregulation of Wnt signaling is also associated with the radioresistance of multiple cancers. Wnts, as important messengers in the tumor microenvironment, are involved in cancer progression mainly via canonical Wnt signaling. Their role in promoting DNA damage repair and inhibiting apoptosis facilitates cancer resistance to radiation. Thus, it seems reasonable to target Wnt signaling as a method for overcoming radioresistance. Many small-molecule inhibitors that target the Wnt signaling pathway have been identified and shown to promote radiosensitization. Therefore, a Wnt signaling inhibitor may help to overcome radioresistance in cancer therapy.

scholarly journals The Regulation of Bone Metabolism and Disorders by Wnt Signaling

2019 ◽  
Vol 20 (22) ◽  
pp. 5525 ◽  
Author(s):  
Kazuhiro Maeda ◽  
Yasuhiro Kobayashi ◽  
Masanori Koide ◽  
Shunsuke Uehara ◽  
Masanori Okamoto ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Wnt Signaling ◽  
Bone Metabolism ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Osteoporosis Treatment ◽  
Biological Phenomena ◽  
Approximate Molecular Weight ◽  
Skeletal Disorders ◽  
Canonical Wnt

Wnt, a secreted glycoprotein, has an approximate molecular weight of 40 kDa, and it is a cytokine involved in various biological phenomena including ontogeny, morphogenesis, carcinogenesis, and maintenance of stem cells. The Wnt signaling pathway can be classified into two main pathways: canonical and non-canonical. Of these, the canonical Wnt signaling pathway promotes osteogenesis. Sclerostin produced by osteocytes is an inhibitor of this pathway, thereby inhibiting osteogenesis. Recently, osteoporosis treatment using an anti-sclerostin therapy has been introduced. In this review, the basics of Wnt signaling, its role in bone metabolism and its involvement in skeletal disorders have been covered. Furthermore, the clinical significance and future scopes of Wnt signaling in osteoporosis, osteoarthritis, rheumatoid arthritis and neoplasia are discussed.

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