Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth.

Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Abstract Text:

Samuel C Falsetti,De-an Wang,Hairuo Peng,Dora Carrico,Adrienne D Cox,Channing J Der,Andrew D Hamilton, Sebti,Samuel C Falsetti,De-an Wang,Hairuo Peng,Dora Carrico,Adrienne D Cox,Channing J Der,Andrew D Hamilton, Sebti,

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.

Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Publishing Authors By Initials

SC Falsetti,DA Wang,H Peng,D Carrico,AD Cox,CJ Der,AD Hamilton,SM Sebti,SC Falsetti,DA Wang,H Peng,D Carrico,AD Cox,CJ Der,AD Hamilton,SM Sebti,

For similar abstracts research abstracts see: abstracts research

PUBMED ID PMID:

MEDLINE DATE:

Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Molecular and cellular biology

VOLUME: 27

Page Numbers: 8003-14

Journal Abbreviation: Mol. Cell. Biol.

ISSN: 1098-5549

DAY: 17

MONTH: 09

YEAR: 2007

Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8109087

Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Keywords Mesh Terms:

KEYWORDS:

MESH TERMS:

Chemical & Substance for Abstract: Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Information

Substance Name:

Registry Number:

Grant and Affiliation Information for Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth.

AFFILIATION: Drug Discovery Program, The H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.

Country: United States

AGENCY: United States NCI

GRANT: U19 CA67771

ACRONYM: CA

MEDLINETA: Mol Cell Biol

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth Related Publications

• Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity.
• Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth.
• Phase I study of alternate-week administration of tipifarnib in patients with myelodysplastic syndrome.