Modulating Angiogenesis

Sivakumar, Branavan; Harry, Lorraine; Paleolog, Ewa

doi:10.1001/jama.292.8.972

Cited by 95 publications

(62 citation statements)

References 51 publications

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“…In addition to potentially suppressing alternate prenylation of K-Ras, the impact of GGTI-DU40 on proteins such as RhoA/C and Cdc42 may prove to be beneficial in limiting oncogenesis by inhibiting proliferation and invasion (36,43,44). Rho activity has a clear function in angiogenesis (45), which in turn plays a critical role in the pathogenesis of tumors, rheumatoid arthritis, atherosclerosis, psoriasis, and diabetic retinopathy (46). In multiple sclerosis, leukocytes and monocytes infiltrate into the central nervous system as part of an inappropriate inflammatory response, and recent evidence suggests that this migration requires Rho signaling and that inhibition of prenylation can lead to decreased inflammatory disease progression (47,48).…”

Section: Discussionmentioning

confidence: 99%

A Novel Protein Geranylgeranyltransferase-I Inhibitor with High Potency, Selectivity, and Cellular Activity

Peterson

Kelly

Weinbaum

et al. 2006

Journal of Biological Chemistry

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Inhibiting protein prenylation is an attractive means to modulate cellular processes controlled by a variety of signaling proteins, including oncogenic proteins such as Ras and Rho GTPases. The largest class of prenylated proteins contain a so-called CaaX motif at their carboxyl termini and are subject to a maturation process initiated by the attachment of an isoprenoid lipid by either protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type I (GGTase-I). Inhibitors of FTase, termed FTIs, have been the subject of intensive development in the past decade and have shown efficacy in clinical trials. Although GGTase-I inhibitors (GGTIs) have received less attention, accumulating evidence suggests GGTIs may augment therapies using FTIs and could be useful to treat a myriad of additional disease states. Here we describe the characterization of a selective, highly potent, and cell-active GGTase-I inhibitor, GGTI-DU40. Kinetic analysis revealed that inhibition by GGTI-DU40 is competitive with the protein substrate and uncompetitive with the isoprenoid substrate; the K i for the inhibition is 0.8 nM. GGTI-DU40 is highly selective for GGTase-I both in vitro and in living cells. Studies indicate GGTI-DU40 blocks prenylation of a number of geranylgeranylated CaaX proteins. Treatment of MDA-MB-231 breast cancer cells with GGTI-DU40 inhibited thrombininduced cell rounding via a process that involves inhibition of Rho proteins without significantly effecting parallel mobilization of calcium via G␤␥. These studies establish GGTI-DU40 as a prime tool for interrogating biologies associated with protein geranylgeranylation and define a novel structure for this emerging class of experimental therapeutics.A promising strategy for the development of anti-cancer drugs is to suppress activation of oncogenic proteins such as Ras superfamily members. Functional Ras proteins require the addition of an isoprenoid lipid via a process directed by a carboxyl-terminal sequence termed the CaaX motif (1, 2), in which a cysteine (C) residue is followed by a dipeptide (aa) that is usually aliphatic and a variable residue (X) that dictates the prenyl group added. An Xaa residue of Ser, Met, Gln, Cys, or Ala directs the addition of the 15-carbon farnesyl lipid, whereas a Leu residue can direct modification by the 20-carbon geranylgeranyl isoprenoid (3). Following addition of the isoprenoid, most CaaX proteins are further processed by the Rce1 protease, which removes the aaX residues and isoprenylcysteine carboxyl methyltransferase (Icmt) 2 to yield a protein containing a carboxyl-terminal isoprenylcysteine carboxyl methylester (4). The CaaX prenyltransferase protein farnesyltransferase (FTase) and protein geranylgeranyltransferase type I (GGTase-I) (5) add either a 15-carbon farnesyl group or a 20-carbon geranylgeranyl group, respectively, to the cysteine found within the CaaX motif. The prenyltransferase holoenzyme consists of an ␣ subunit that is shared between the two forms of enzymes and a distinct ␤ subunit that binds sub...

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Section: Discussionmentioning

confidence: 99%

A Novel Protein Geranylgeranyltransferase-I Inhibitor with High Potency, Selectivity, and Cellular Activity

Peterson

Kelly

Weinbaum

et al. 2006

Journal of Biological Chemistry

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“…It also assists in the development of granulation tissue formation and ultimately wound closure. Both angiogenic agonists and antagonists are identified at various stages of the wound repair process, 52,53 suggesting a dynamic balance of stimulators and inhibitors that favor either vascular growth or regression. 54 Anti-angiogenic agents may delay the healing of wounds.…”

Section: Discussionmentioning

confidence: 99%

Recruitment of a Prostaglandin E Receptor Subtype, EP3-Expressing Bone Marrow Cells Is Crucial in Wound-Induced Angiogenesis

Kamoshita

Ikeda

Fujita

et al. 2006

The American Journal of Pathology

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E-type prostaglandins have been reported to be proangiogenic in vivo. Thus, we examined prostaglandin receptor signaling relevant to wound-induced angiogenesis. Full-thickness skin wounds were created on the backs of mice, and angiogenesis in wound granulation tissues was estimated. Wound closure and re-epithelization in EP3 receptor knockout mice (EP3 ؊/؊ ) were significantly delayed compared with their wild-type (WT) mice, whereas those in EP1 ؊/؊ , EP2 ؊/؊ , and EP4 ؊/؊ were not delayed. Wound-induced angiogenesis estimated with CD31 immunohistochemistry in EP3 ؊/؊ mice was significantly inhibited compared with that in WT mice. Immunoreactive vascular endothelial growth factor (VEGF) in wound granulation tissues in EP3 ؊/؊ mice was markedly less than that in WT mice. Wound closure in WT mice was delayed significantly by VEGF neutralizing antibody compared with control IgG. Wound-induced angiogenesis and wound closure were significantly suppressed in EP3 ؊/؊ bone marrow transplantation mice compared with those in WT bone marrow transplantation mice. These were accompanied with the reductions in accumulation of VEGF-expressing cells in wound granulation tissues and in mobilization of VEGF receptor 1-expressing leukocytes in peripheral circulation. These results indicate that the recruitment of EP3-expressing cells to wound granulation tissues is critical for surgical wound healing and angiogenesis via up-regulation of VEGF. (Am J Pathol

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“…39 Therefore, promoting myocardial angiogenesis may have an impact beyond the obvious benefit of oxygen and blood supply. Although clinical trials of myocardial therapeutic angiogenesis have largely been disappointing to date, 40 this may be caused by inadequate controls on dose and control of delivery. 41 Biomaterial-based angiogenic protein delivery offers promise for better control of local therapeutic angiogenesis.…”

Section: Delivery Of Angiogenic Factorsmentioning

confidence: 99%