National Cancer Institute researcher Eric Huang and colleagues have identified a mechanism that promotes mutations under hypoxic conditions.1 The oxygen-deprived microenvironment of certain tumors causes genetic instabilities that stimulate tumor progression and metastasis.
Huang's team found that, under certain cellular conditions, the hypoxia-induced transcription factor HIF-1α is responsible for hindering the cell's mismatch repair (MMR) system, crucial for maintaining genetic integrity.
Working with various human cancer cell lines, the group found that HIF-1α acts by displacing Myc, the transcriptional activator of two nuclear proteins, MSH2 and MSH6. In the absence of HIF-1α, Myc activates the expression of the two compounds, which then dimerize to form the MutSα complex – one of the mammalian versions of the MMR system. In the presence of HIF-1α, Myc cannot reach the promoters, and the expression of MutSα is inhibited.
They also found that p53 is essential for the pathway to proceed. Yale University geneticist ...
