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Identifying the ubiquitin ligase complex that regulates the NF1 tumor suppressor and Ras
| Content Provider | PubMed Central |
|---|---|
| Author | Hollstein, Pablo E. Cichowski, Karen |
| Abstract | The NF1 tumor suppressor protein, neurofibromin, is a negative regulator of Ras. Neurofibromin is dynamically regulated by the proteasome and its degradation and re-expression 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)/KBTBD7 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 ERK, and inhibit proliferation in an NF1-dependent manner. Moreover, in glioblastomas where neurofibromin is chronically destabilized, Cul3 inhibition re-stabilizes the protein and suppresses tumor development. Collectively these studies demonstrate a previously unrecognized role for Cul3 in regulating Ras and provide a molecular framework that can be exploited to develop potential cancer therapies. |
| Related Links | http://dx.doi.org/10.1158/2159-8290.cd-13-0146 |
| File Format | |
| ISSN | 21598274 |
| e-ISSN | 21598290 |
| Journal | Cancer discovery |
| Issue Number | 8 |
| Volume Number | 3 |
| Language | English |
| Publisher Date | 2013-08-01 |
| Access Restriction | Open |
| Subject Keyword | Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Oncology |
