title: Identifying the Ubiquitin Ligase complex that regulates the NF1 tumor suppressor and Ras.
abstract: The NF1 tumor suppressor protein neurofibromin is a negative regulator of Ras. Neurofibromin is dynamically regulated by the proteasome, and its degradation and reexpression are essential for maintaining appropriate levels of Ras-GTP. Like p53, NF1/neurofibromin can be inactivated in cancer by both mutations and excessive proteasomal destruction; however, little is known about the mechanisms that underlie this latter process. Here, we show that a Cullin 3 (Cul3)/kelch repeat and BTB domain-containing 7 complex controls both the regulated proteasomal degradation of neurofibromin and the pathogenic destabilization of neurofibromin in glioblastomas. Importantly, RNAi-mediated Cul3 ablation and a dominant-negative Cul3 directly stabilize neurofibromin, suppress Ras and extracellular signal-regulated kinase, and inhibit proliferation in an NF1-dependent manner. Moreover, in glioblastomas where neurofibromin is chronically destabilized, Cul3 inhibition restabilizes the protein and suppresses tumor development. Collectively, these studies show a previously unrecognized role for Cul3 in regulating Ras and provide a molecular framework that can be exploited to develop potential cancer therapies.
authors: Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, NRB 0458C, Boston, MA 02115, USA.
authors: Pablo E
authors: PE
authors: Hollstein
authors: Karen
authors: K
authors: Cichowski
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D015534:Trans-Activators / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D054875:Ubiquitination; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C503645:CUL3 protein, human; D044842:Cullin Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C549143:KBTBD7 protein, human; D025542:Neurofibromin 1; D015534:Trans-Activators; D043743:Ubiquitin-Protein Ligase Complexes; D046988:Proteasome Endopeptidase Complex; D018631:ras Proteins
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