NOTHING IN EXCESS - LESSONS LEARNED FROM THE EXPRESSION OF HIGH-MOBILITY GROUP PROTEINS TYPE A IN NON-CANCER AND CANCER CELLS

摘要

High-mobility group A (HMGA) proteins are major transcription regulators which are abundantly and ubiquitously expressed in undifferentiated cells but present at a low level in somatic cells of adult organisms. Up-regulation of HMGA expression is a frequent finding in cancer, either via direct stimulation of expression by constitutively expressed proto-oncogenic factors such as MYC and JUNor by rearrangements rendering the expression of the HMGA proteins not suppressive by inhibitory factors such asmiRNAs. Rearrangements of the HMGA genomic loci resulting in disabling of the control mechanisms of their expression are often seen in tumours of various origin. A direct relationship between the level of expression of HMGA in mitochondria and the levelof accumulation of oxidative damage in cancer cells has been recently noted. On the other hand, mammalian cells deficient in HMGA 1 expression are also deficient in utilization of glucose and show the impairment in expression of the insulin receptor andthe high levels of oxidative damage of DNA characteristic of diabetes type 2 and the related condition metabolic syndrome. Insulin resistance and metabolic syndrome could be viewed as a premalignant state in which DNA damage is slowly accumulating untilthe repair machinery of the cell cannot withstand the constant oxidative barrage and surrenders to neoplastic transformation.