ArticleMolecular and cellular biology2009
Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy.
Article in Molecular and cellular biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 62 citations in OpenAlex.
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- Targeting the cytoskeleton against metastatic dissemination.Cancer metastasis reviews · 2021Review
- Polyisoprenylated Cysteinyl Amide Inhibitors: A Novel Approach to Controlling Cancers with Hyperactive Growth Signaling.Current medicinal chemistry · 2021Article
- Small molecule inhibitors of RAS proteins with oncogenic mutations.Cancer metastasis reviews · 2020Review
- Increased flux through the mevalonate pathway mediates fibrotic repair without injury.The Journal of clinical investigation · 2019Article
- A Phase I Study of GGTI-2418 (Geranylgeranyl Transferase I Inhibitor) in Patients with Advanced Solid Tumors.Targeted oncology · 2019Article
- Isoprenoids and protein prenylation: implications in the pathogenesis and therapeutic intervention of Alzheimer's disease.Critical reviews in biochemistry and molecular biology · 2018Review
- Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies.Chemical reviews · 2018Article
- PTEN counteracts FBXL2 to promote IP3R3- and CaNature · 2017Article
- The Role of Geranylgeranyltransferase I-Mediated Protein Prenylation in the Brain.Molecular neurobiology · 2016Review
- Selective Gas-Phase Oxidation and Localization of Alkylated Cysteine Residues in Polypeptide Ions via Ion/Ion Chemistry.Journal of proteome research · 2016Article
- CRM-1 knockdown inhibits extrahepatic cholangiocarcinoma tumor growth by blocking the nuclear export of p27Kip1.International journal of molecular medicine · 2016Article
- The non-canonical functions of p27(Kip1) in normal and tumor biology.Cell cycle (Georgetown, Tex.) · 2016Review
- Statin-induced depletion of geranylgeranyl pyrophosphate inhibits cell proliferation by a novel pathway of Skp2 degradation.Oncotarget · 2015Article
- Modulation of the mevalonate pathway by akt regulates macrophage survival and development of pulmonary fibrosis.The Journal of biological chemistry · 2014Article
- Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease.Pharmacology & therapeutics · 2014Review
- Expression of p27Kip1, a cell cycle repressor protein, is inversely associated with potential carcinogenic risk in the genetic rodent models of obesity and long-lived Ames dwarf mice.Metabolism: clinical and experimental · 2013Article
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
We describe the design of a potent and selective peptidomimetic inhibitor of geranylgeranyltransferase I (GGTI), GGTI-2418, and its methyl ester GGTI-2417, which increases the levels of the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) and induces breast tumor regression in vivo. Experiments with p27(Kip1) small interfering RNA in breast cancer cells and p27(Kip1) null murine embryonic fibroblasts demonstrate that the ability of GGTI-2417 to induce cell death requires p27(Kip1). GGTI-2417 inhibits the Cdk2-mediated phosphorylation of p27(Kip1) at Thr187 and accumulates p27(Kip1) in the nucleus. In nude mouse xenografts, GGTI-2418 suppresses the growth of human breast tumors. Furthermore, in ErbB2 transgenic mice, GGTI-2418 increases p27(Kip1) and induces significant regression of breast tumors. We conclude that GGTIs' antitumor activity is, at least in part, due to inhibiting Cdk2-dependent p27(Kip1) phosphorylation at Thr187 and accumulating nuclear p27(Kip1). Thus, GGTI treatment might improve the poor prognosis of breast cancer patients with low nuclear p27(Kip1) levels.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.