scholarly journals Geranylgeranyltransferase I Inhibitor

2020 ◽  
Author(s):  
Keyword(s):  
Geranylgeranyltransferase I

scholarly journals Suppressive Role of Bam32/DAPP1 in Chemokine-Induced Neutrophil Recruitment

2021 ◽  
Vol 22 (4) ◽  
pp. 1825
Author(s):  
Li Hao ◽  
Aaron J. Marshall ◽  
Lixin Liu
Keyword(s):  
Small Gtpases ◽  
Neutrophil Recruitment ◽  
Neutrophil Chemotaxis ◽  
Wild Type ◽  
Adaptor Molecule ◽  
Geranylgeranyltransferase I ◽  
And Migration ◽  
Rap1 Activation

Bam32 (B cell adaptor molecule of 32 kDa) functions in the immune responses of various leukocytes. However, the role of neutrophil Bam32 in inflammation is entirely unknown. Here, we determined the role of Bam32 in chemokine CXCL2-induced neutrophil chemotaxis in three mouse models of neutrophil recruitment. By using intravital microscopy in the mouse cremaster muscle, we found that transmigrated neutrophil number, neutrophil chemotaxis velocity, and total neutrophil chemotaxis distance were increased in Bam32−/− mice when compared with wild-type (WT) mice. In CXCL2-induced mouse peritonitis, the total emigrated neutrophils were increased in Bam32−/− mice at 2 but not 4 h. The CXCL2-induced chemotaxis distance and migration velocity of isolated Bam32−/− neutrophils in vitro were increased. We examined the activation of small GTPases Rac1, Rac2, and Rap1; the levels of phospho-Akt2 and total Akt2; and their crosstalk with Bam32 in neutrophils. The deficiency of Bam32 suppressed Rap1 activation without changing the activation of Rac1 and Rac2. The pharmacological inhibition of Rap1 by geranylgeranyltransferase I inhibitor (GGTI298) increased WT neutrophil chemotaxis. In addition, the deficiency of Bam32, as well as the inhibition of Rap1 activation, increased the levels of CXCL2-induced Akt1/2 phosphorylation at Thr308/309 in neutrophils. The inhibition of Akt by SH-5 attenuated CXCL2-induced adhesion and emigration in Bam32−/− mice. Together, our results reveal that Bam32 has a suppressive role in chemokine-induced neutrophil chemotaxis by regulating Rap1 activation and that this role of Bam32 in chemokine-induced neutrophil recruitment relies on the activation of PI3K effector Akt.

scholarly journals Inactivation of farnesyltransferase and geranylgeranyltransferase I by caspase-3: Cleavage of the common α subunit during apoptosis

Oncogene ◽  
2001 ◽  
Vol 20 (3) ◽  
pp. 358-366 ◽  
Author(s):  
Ki-Woo Kim ◽  
Hyun-Ho Chung ◽  
Chul-Woong Chung ◽  
In-Ki Kim ◽  
Masayuki Miura ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Α Subunit ◽  
Geranylgeranyltransferase I ◽  
The Common

scholarly journals Geranylgeranyltransferase I Inhibitors Target RalB To Inhibit Anchorage-Dependent Growth and Induce Apoptosis and RalA To Inhibit Anchorage-Independent Growth

2007 ◽  
Vol 27 (22) ◽  
pp. 8003-8014 ◽  
Author(s):  
Samuel C. Falsetti ◽  
De-an Wang ◽  
Hairuo Peng ◽  
Dora Carrico ◽  
Adrienne D. Cox ◽  
...  
Keyword(s):  
Small Gtpases ◽  
Wild Type ◽  
Anchorage Independent Growth ◽  
Protein Levels ◽  
Survival Pathways ◽  
Tumor Survival ◽  
Geranylgeranyltransferase I ◽  
Ral Gtpases ◽  
Carboxyl Terminal ◽  
Dependent Growth

ABSTRACT Geranylgeranyltransferase I inhibitors (GGTIs) are presently undergoing advanced preclinical studies and have been shown to disrupt oncogenic and tumor survival pathways, to inhibit anchorage-dependent and -independent growth, and to induce apoptosis. However, the geranylgeranylated proteins that are targeted by GGTIs to induce these effects are not known. Here we provide evidence that the Ras-like small GTPases RalA and RalB are exclusively geranylgeranylated and that inhibition of their geranylgeranylation mediates, at least in part, the effects of GGTIs on anchorage-dependent and -independent growth and tumor apoptosis. To this end, we have created the corresponding carboxyl-terminal mutants that are exclusively farnesylated and verified that they retain the subcellular localization and signaling activities of the wild-type geranylgeranylated proteins and that Ral GTPases do not undergo alternative prenylation in response to GGTI treatment. By expressing farnesylated, GGTI-resistant RalA and RalB in Cos7 cells and human pancreatic MiaPaCa2 cancer cells followed by GGTI-2417 treatment, we demonstrated that farnesylated RalB, but not RalA, confers resistance to the proapoptotic and anti-anchorage-dependent growth effects of GGTI-2417. Conversely, farnesylated RalA but not RalB expression renders MiaPaCa2 cells less sensitive to inhibition of anchorage-independent growth. Furthermore, farnesylated RalB, but not RalA, inhibits the ability of GGTI-2417 to suppress survivin and induce p27 Kip1 protein levels. We conclude that RalA and RalB are important, functionally distinct targets for GGTI-mediated tumor apoptosis and growth inhibition.

Synthesis and evaluation of potent, highly-selective, 3-aryl-piperazinone inhibitors of protein geranylgeranyltransferase-I

2006 ◽  
Vol 4 (9) ◽  
pp. 1768 ◽  
Author(s):  
Hairuo Peng ◽  
Dora Carrico ◽  
Van Thai ◽  
Michelle Blaskovich ◽  
Cynthia Bucher ◽  
...  
Keyword(s):  
Geranylgeranyltransferase I

Genetic evidence for in vivo cross-specificity of the CaaX-box protein prenyltransferases farnesyltransferase and geranylgeranyltransferase-I in Saccharomyces cerevisiae

1993 ◽  
Vol 13 (7) ◽  
pp. 4260-4275
Author(s):  
C E Trueblood ◽  
Y Ohya ◽  
J Rine
Keyword(s):  
Genetic Data ◽  
Yeast Cells ◽  
Covalent Attachment ◽  
Ras Proteins ◽  
Substrate Preferences ◽  
Geranylgeranyltransferase I ◽  
Altered Form ◽  
Protein Prenyltransferases

Two protein prenyltransferase enzymes, farnesyltransferase (FTase) and geranylgeranyltransferase-I (GGTase-I), catalyze the covalent attachment of a farnesyl or geranylgeranyl lipid group to the cysteine of a CaaX sequence (cysteine [C], two aliphatic amino acids [aa], and any amino acid [X]. In vitro studies reported here confirm previous reports that CaaX proteins with a C-terminal serine are farnesylated by FTase and those with a C-terminal leucine are geranylgeranylated by GGTase-I. In addition, we found that FTase can farnesylate CaaX proteins with a C-terminal leucine and can transfer a geranylgeranyl group to some CaaX proteins. Genetic data indicate that FTase and GGTase-I have the same substrate preferences in vivo as in vitro and also show that each enzyme can prenylate some of the preferred substrates of the other enzyme in vivo. Specifically, the viability of yeast cells lacking FTase is due to prenylation of Ras proteins by GGTase-I. Although this GGTase-I dependent prenylation of Ras is sufficient for growth, it is not sufficient for mutationally activated Ras proteins to exert deleterious effects on growth. The dependence of the activated Ras phenotype on FTase can be bypassed by replacing the C-terminal serine with leucine. This altered form of Ras appears to be prenylated by both GGTase-I and FTase, since it produces an activated phenotype in a strain lacking either FTase or GGTase-I. Yeast cells can grow in the absence of GGTase-I as long as two essential substrates are overexpressed, but their growth is slow. Such strains are dependent on FTase for viability and are able to grow faster when FTase is overproduced, suggesting that FTase can prenylate the essential substrates of GGTase-I when they are overproduced.

scholarly journals Protein geranylgeranyltransferase-I of Trypanosoma cruzi

2008 ◽  
Vol 157 (1) ◽  
pp. 32-43 ◽  
Author(s):  
Kohei Yokoyama ◽  
John R. Gillespie ◽  
Wesley C. Van Voorhis ◽  
Frederick S. Buckner ◽  
Michael H. Gelb
Keyword(s):  
Trypanosoma Cruzi ◽  
Geranylgeranyltransferase I

Abstract 2605: The geranylgeranyltransferase I inhibitor GGTI-2418 suppresses multiple myeloma malignancy in the 5TMG1 mouse model

2015 ◽  
Author(s):  
Hua Yang ◽  
Michael F. Emmons ◽  
Christopher Cubitt ◽  
Ken Shain ◽  
Domenico Coppola ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mouse Model ◽  
Geranylgeranyltransferase I

Aryloxy substituted N-arylpiperazinones as dual inhibitors of farnesyltransferase and geranylgeranyltransferase-I

2001 ◽  
Vol 11 (11) ◽  
pp. 1411-1415 ◽  
Author(s):  
Jeffrey M Bergman ◽  
Marc T Abrams ◽  
Joseph P Davide ◽  
Ian B Greenberg ◽  
Ronald G Robinson ◽  
...  
Keyword(s):  
Geranylgeranyltransferase I ◽  
Dual Inhibitors
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