Figure 1.

Progressive inactivation of GSK3β may promote accelerated cell cycle and oral cancer. As discussed in the text, most of the cell cycle regulators and their gain of function may be because of inactivation of GSK3β in oral cancer. GSK3β regulates the activity or turnover of several master cell cycle regulators like p53. Activation of p21, 14-3-3σ and GADD45 protein by p53 induces cell cycle arrest to prevent the propagation of mutations, which accumulate in cells under genotoxic stress. p53 induces the expression of the cytoplasmic scaffold protein 14-3-3σ, which prevents the nuclear import of cyclin B1 and cdc2 by sequestration in the cytoplasm. On the other hand, GADD45 destabilizes CDC2/cyclinB complexes. GSK3β-regulated c-Myc is a master regulator of the cell cycle and is essential for G0/G1-to-S progression. Myc suppresses the expression of cell cycle checkpoint genes (GADD45, GADD153) and inhibits the function of CDK inhibitors. Myc also activates cyclins D1, E1, and A2, CDK4, CDC25A, and E2F-1 and -2. Cyclin D1 is a crucial cell cycle regulator mainly regulated by the activity of TFs (NFκB, β-catenin-TCF/LEF, AP-1) and is indirectly controlled by GSK3β. Moreover, inactivation of GSK3β leads to the stabilization of cyclin D1. Oncogenic gains of function of these molecules stemming from inactive GSK3β have been established in various neoplastic diseases and might orchestrate cell cycle dysregulation in OSCC.

Mishra Molecular Cancer 2010 9:144   doi:10.1186/1476-4598-9-144
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