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Researchers find coupling of proteins promotes glioblastoma development
Date:10/21/2011

that is processed into a protein.

Structural analysis led Huang and her team to suspect FoxM1 might be a binding match for beta-catenin, a crucial protein in the Wnt signaling pathway, which regulates self-renewal and differentiation of neural stem cells. When a normal cell divides, it produces two copies of itself. A neural stem cell produces one copy of itself (self-renewal) and a copy of a functional brain cell, such as a neuron or an astrocyte (differentiation). Mutations occur in the Wnt pathway in other types of cancer, but are largely absent in glioblastoma.

Blocking either FoxM1 or beta-catenin function strongly influenced whether mice injected with glioblastoma cells developed brain tumors. Most dramatically, blocking FoxM1 with short hairpin RNA completely prevented development of brain tumors in 38 mice, while all 20 with unimpeded FoxM1 developed tumors.

In a series of cell line experiments leading to the mouse model research, the group found:

  • FoxM1 is expressed at high levels in glioma and in glioma-initiating cells.
  • FoxM1 and beta-catenin bind to each other in tumor cells.
  • Wnt promotes the movement of both FoxM1 and beta-catenin to the cell nucleus.
  • FoxM1 is required for beta-catenin to move to the cell nucleus in both neural stem cells and in tumor cells.
  • The FoxM1 and beta-catenin connection is required for transcription and expression of beta-catenin Wnt- targeted genes in the nucleus.
  • Interaction between the two proteins is critical to both cell renewal and differentiation in glioma stem cells.

The team analyzed 40 glioblastoma samples and found FoxM1 moderately expressed in 14 and highly expressed in 18. Levels of FoxM1 in the cell nucleus correlated directly with levels of beta-catenin expression and the expression of two Wnt target genes.

Additional analysis of eight tumors found the two proteins present together in the cell nuclei and a direct corre
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

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