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Loss of p53 cooperates with K-ras activation to induce glioma formation in a region-independent manner.

Authors: Muñoz, Diana Marcela  Tung, Takyee  Agnihotri, Sameer  Singh, Sanjay  Guha, Abhijit  Zadeh, Gelareh  Hawkins, Cynthia 
Citation: Muñoz DM, etal., Glia. 2013 Nov;61(11):1862-72. doi: 10.1002/glia.22563. Epub 2013 Aug 30.
Pubmed: (View Article at PubMed) PMID:24038521
DOI: Full-text: DOI:10.1002/glia.22563

Gliomas are recognized as a heterogeneous group of neoplasms differing in their location and morphological features. These differences, between and within varying grades of gliomas, have not been explained solely on the grounds of an oncogenic stimulus. Interactions with the tumor microenvironment as well as inherent characteristics of the cell of origin are likely a source of this heterogeneity. There is an ongoing debate over the cell of origin of gliomas, where some suggest a progenitor, while others argue for a stem cell origin. Thus, it is presumed that neurogenic regions of the brain such as the subventricular zone (SVZ) containing large numbers of neural stem and progenitor populations are more susceptible to transformation. Our studies demonstrate that K-ras(G12D) cooperates with the loss of p53 to induce gliomas from both the SVZ and cortical region, suggesting that cells in the SVZ are not uniquely gliomagenic. Using combinations of doxycycline-inducible K-ras(G12D) and p53 loss, we show that tumors induced by the cooperative actions of these genes remain dependent on active K-ras expression, as deinduction of K-ras(G12D) leads to complete tumor regression despite absence of p53. These results suggest that the interplay between specific combinations of genetic alterations and susceptible cell types, rather than the site of origin, are important determinates of gliomagenesis. Additionally, this model supports the view that, although several genetic events may be necessary to confer traits associated with oncogenic transformation, inactivation of a single oncogenic partner can undermine tumor maintenance, leading to regression and disease remission.


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CRRD Object Information
CRRD ID: 13702858
Created: 2018-07-19
Species: All species
Last Modified: 2018-07-19
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.