scholarly journals Chebulinic Acid Suppresses Adipogenesis in 3T3-L1 Preadipocytes by Inhibiting PPP1CB Activity

2022 ◽  
Vol 23 (2) ◽  
pp. 865
Author(s):  
Jinsoo Kim ◽  
Dohee Ahn ◽  
Sang J. Chung
Keyword(s):  
Transcription Factors ◽  
Therapeutic Target ◽  
Protein Phosphatase ◽  
Therapeutic Agent ◽  
Protein Phosphatase 1 ◽  
Dependent Manner ◽  
Terminalia Chebula ◽  
Potential Therapeutic Target ◽  
Concentration Dependent Manner ◽  
Hydrolysis Of

Depletion of protein phosphatase-1 catalytic subunit beta (PPP1CB), a serine/threonine protein phosphatase and potent adipogenic activator, suppresses the differentiation of 3T3-L1 preadipocytes into mature adipocytes. Therefore, PPP1CB is considered as a potential therapeutic target for obesity. We screened 1033 natural products for PPP1CB inhibitors and identified chebulinic acid, which is abundantly present in the seeds of Euphoria longana and fruits of Terminalia chebula. Chebulinic acid strongly inhibited the hydrolysis of 6,8-difluoro-4-methylumbelliferyl phosphate by PPP1CB (IC50 = 300 nM) and demonstrated potent antiadipogenic effects in 3T3-L1 preadipocytes in a concentration-dependent manner. Additional studies have demonstrated that chebulinic acid suppresses early differentiation by downregulating key transcription factors that control adipogenesis in 3T3-L1 cells. These results suggested that chebulinic acid may be a potential therapeutic agent for treating obesity by inhibiting PPP1CB activity.

Identification of transcription factors associated with castration-resistance: Is the serum responsive factor a potential therapeutic target?

The Prostate ◽  
2013 ◽  
Vol 73 (7) ◽  
pp. 743-753 ◽  
Author(s):  
Maria Prencipe ◽  
Stephen F. Madden ◽  
Amanda O'Neill ◽  
Gillian O'Hurley ◽  
Aedin Culhane ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Therapeutic Target ◽  
Castration Resistance ◽  
Potential Therapeutic Target ◽  
Factors Associated

Serine/threonine protein phosphatase 5 is a potential therapeutic target in cholangiocarcinoma

2018 ◽  
Vol 38 (12) ◽  
pp. 2248-2259 ◽  
Author(s):  
Ming-Hung Hu ◽  
Tzu-Ting Huang ◽  
Tzu-I Chao ◽  
Li-Ju Chen ◽  
Yen-Lin Chen ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Protein Phosphatase ◽  
Potential Therapeutic Target ◽  
Protein Phosphatase 5

scholarly journals Lysine and Polyamines Are Substrates for Transglutamination of Rho by the BordetellaDermonecrotic Toxin

2001 ◽  
Vol 69 (12) ◽  
pp. 7663-7670 ◽  
Author(s):  
Gudula Schmidt ◽  
Udo-Michael Goehring ◽  
Joerg Schirmer ◽  
Sandrine Uttenweiler-Joseph ◽  
Matthias Wilm ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Affinity Purification ◽  
Dependent Manner ◽  
Rho Proteins ◽  
Concentration Dependent Manner ◽  
Gtp Hydrolysis ◽  
Dermonecrotic Toxin ◽  
Hydrolysis Of ◽  
Active Fragment

ABSTRACT Bordetella dermonecrotic toxin (DNT) catalyzes the transglutamination of glutamine-63/61 of Rho GTPases, thereby constitutively activating Rho proteins. Here we identified second substrates for transglutamination of RhoA by DNT. The enzymatically active fragment of DNT (residues 1136 to 1451, ΔDNT) induced the incorporation of l-[14C]lysine in RhoA in a concentration-dependent manner. Also, Rac and Cdc42, but not Ras, were transglutaminated with lysine by ΔDNT. Transglutamination of the GTPase with l-lysine inhibited intrinsic and Rho-GAP-stimulated GTP hydrolysis of RhoA. In contrast to lysine, treatment of RhoA with alanine, arginine, and glutamine were not able to substitute for lysine in the transglutamination reaction. DNT increased the incorporation of l-[14C]lysine into embryonic bovine lung cells. Microinjection of GST-RhoA together with the enzymatically active DNT fragment intoXenopus oocytes, subsequent affinity purification of modified GST-RhoA, and mass spectrometry identified attachment of putrescine or spermidine at glutamine-63 of RhoA. A comparison of putrescine, spermidine, and lysine as substrates for DNT-induced transglutamination of RhoA revealed that lysine is a preferred second substrate at least in vitro.

STEM-14. THE WRAD COMPLEX REPRESENTS A THERAPEUTIC TARGET FOR CANCER STEM CELLS IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi23-vi24
Author(s):  
Kelly Mitchell ◽  
Joseph Alvarado ◽  
Christopher Goins ◽  
Steven Martinez ◽  
Jonathan Macdonald ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Transcription Factors ◽  
Cancer Stem Cells ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Self Renewal ◽  
Stem Cell Maintenance ◽  
Cell Maintenance

Abstract Glioblastoma (GBM) progression and resistance to conventional therapies is driven in part by cells within the tumor with stem cell properties including quiescence, self-renewal and drug efflux potential. It is thought that eliminating these cancer stem cells (CSCs) is a key component to successful clinical management of GBM. However, currently, few known molecular mechanisms driving CSCs can be exploited for therapeutic development. Core transcription factors such as SOX2, OLIG2, OCT4 and NANOG maintain the CSC state in GBM. Our laboratory recently uncovered a self-renewal signaling axis involving RBBP5 that is necessary and sufficient for CSC maintenance through driving expression of these core stem cell maintenance transcription factors. RBBP5 is a component of the WRAD complex, which promotes Lys4 methylation of histone H3 to positively regulate transcription. We hypothesized that targeting RBBP5 could be a means to disrupt epigenetic programs that maintain CSCs in stemness transcriptional states. We found that genetic and pharmacologic inhibition of the WRAD complex reduced CSC growth, self-renewal and tumor initiation potential. WRAD inhibitors partially dissembled the WRAD complex and reduced H3K4 trimethylation both globally and at the promoters of key stem cell maintenance transcription factors. Using a CSC reporter system, we demonstrated that WRAD complex inhibition decreased growth of SOX2/OCT4 expressing CSCs in a concentration-dependent manner as quantified by live imaging. Overall, our studies assess the function of the WRAD complex and the effect of WRAD complex inhibitors in preclinical models and specifically on the stem cell state for the first time in GBM. Studying the functions of the WRAD complex in CSCs may improve understanding of GBM pathogenesis and elucidate how CSCs survive despite aggressive chemotherapy and radiation. Our ongoing studies aim to develop brain penetrant inhibitors targeting the WRAD complex as an anti-CSC strategy that could potentially synergize with standard of care treatments.

scholarly journals Inhibition of MMP-2 gelatinolysis by targeting exodomain–substrate interactions

2007 ◽  
Vol 406 (1) ◽  
pp. 147-155 ◽  
Author(s):  
Xiaoping Xu ◽  
Zhihua Chen ◽  
Yao Wang ◽  
Lynda Bonewald ◽  
Bjorn Steffensen
Keyword(s):  
Binding Site ◽  
Type I Collagen ◽  
Matrix Metalloproteinase 2 ◽  
Type I ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Collagen Binding ◽  
Collagen Peptides ◽  
Collagen Chain ◽  
Hydrolysis Of

MMP-2 (matrix metalloproteinase 2) contains a CBD (collagen-binding domain), which is essential for positioning gelatin substrate molecules relative to the catalytic site for cleavage. Deletion of the CBD or disruption of CBD-mediated gelatin binding inhibits gelatinolysis by MMP-2. To identify CBD-binding sites on type I collagen and collagen peptides with the capacity to compete CBD binding of gelatin and thereby inhibit gelatinolysis by MMP-2, we screened a one-bead one-peptide combinatorial peptide library with recombinant CBD as bait. Analyses of sequences from the CBD-binding peptides pointed to residues 715–721 in human α1(I) collagen chain as a binding site for CBD. A peptide (P713) including this collagen segment was synthesized for analyses. In SPR (surface plasmon resonance) assays, the CBD and MMP-2E404A, a catalytically inactive MMP-2 mutant, both bound immobilized P713 in a concentration-dependent manner, but not a scrambled control peptide. Furthermore, P713 competed gelatin binding by the CBD and MMP-2E404A. In control assays, neither of the non-collagen binding alkylated CBD or MMP-2 with deletion of CBD (MMP-2ΔCBD) bound P713. Consistent with the exodomain functions of the CBD, P713 inhibited ∼90% of the MMP-2 gelatin cleavage, but less than 20% of the MMP-2 activity on a peptide substrate (NFF-1) which does not require the CBD for cleavage. Confirming the specificity of the inhibition, P713 did not alter MMP-2ΔCBD or MMP-8 activities. These experiments identified a CBD-binding site on type I collagen and demonstrated that a corresponding synthetic peptide can inhibit hydrolysis of type I and IV collagens by competing CBD-mediated gelatin binding to MMP-2.

scholarly journals The microRNA cluster miR-183/96/182 contributes to long-term memory in a protein phosphatase 1-dependent manner

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Bisrat T. Woldemichael ◽  
Ali Jawaid ◽  
Eloïse A. Kremer ◽  
Niharika Gaur ◽  
Jacek Krol ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Long Term Memory ◽  
Dependent Manner ◽  
Term Memory ◽  
Microrna Cluster

scholarly journals IPP5, a novel protein inhibitor of protein phosphatase 1, promotes G1/S progression in a Thr-40-dependent manner.

2015 ◽  
Vol 290 (10) ◽  
pp. 6004-6004
Author(s):  
Xiaojian Wang ◽  
Bin Liu ◽  
Nan Li ◽  
Hongzhe Li ◽  
Jianming Qiu ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Dependent Manner ◽  
Protein Inhibitor ◽  
Novel Protein

Effects of okadaic acid and intracellular Cl- on Na(+)-K(+)-Cl- cotransport

1995 ◽  
Vol 269 (4) ◽  
pp. C878-C883 ◽  
Author(s):  
A. A. Altamirano ◽  
G. E. Breitwieser ◽  
J. M. Russell
Keyword(s):  
Phosphatase Activity ◽  
Okadaic Acid ◽  
Protein Phosphatase ◽  
Giant Axon ◽  
Subsequent Treatment ◽  
Squid Giant Axon ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Intracellular Atp ◽  
Phosphatase Inhibitor

The Na(+)-K(+)-Cl- cotransporter of the squid giant axon requires ATP and is inhibited by intracellular Cl- (Cli-) in a concentration-dependent manner ([Cl-]i > or = 200 mM completely inhibits the cotransporter). In the present study we address the question of whether inhibition of cotransport by Cli- is due to a Cl(i-)-induced increase of protein phosphatase activity. Intracellular dialysis was used to apply the phosphatase inhibitor okadaic acid (OKA) under conditions of [Cl-]i at 0, 150, or 300 mM during measurement of cotransporter-mediated unidirectional Cl- influx into axons. At 0 mM [Cl-]i, the application of 250 nM OKA had no effect on the cotransport-mediated Cl- influx when axons were dialyzed with the normal intracellular ATP concentration ([ATP]i = 4 mM). Reduction of [ATP] to 50 microM resulted in a significant decrease of the bumetanide-sensitive CL- influx, which could be partially reversed by OKA treatment. Similarly, in ATP-limited axons with [Cl-]i at 150 mM, cotransporter influx was partially stimulated by treatment with OKA. However, axons dialyzed with 300 mM [Cl-]i ([ATP]i = 50 microM) had no measurable cotransport influx, nor was subsequent treatment with OKA able to induce a cotransport-mediated Cl- influx. We conclude that the inhibition of cotransport caused by Cli- is not the result of an increase in the OKA-sensitive protein phosphatase activity.

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