p53 not effective in hibernation Free

When the temperature begins to fall and the days draw in, some animals opt for hibernation to conserve energy, which means cutting back on many costly metabolic processes. According to Peipei Pan and Frank van Breukelen, from the University of Nevada, Las Vegas, USA, the key process of transcription – where genes are transcribed from DNA to messenger RNA (mRNA) prior to translation into proteins – is extremely costly, so it is virtually arrested in hibernating animals. However, proteins that control the process of transcription (transcription factors) move in and out of the nucleus while an animal is hibernating, which puzzled Pan and van Breukelen. What could these transcription factors be doing when transcription in the cells of hibernating animals is essentially shut down? The duo decided to investigate the regulation of p53, a key protein that regulates many essential cellular processes, in hibernating golden-mantled ground squirrels to find out how transcription factors function in hibernating tissue (p. 2489).

‘p53 is a really cool protein. It sits at the crossroads of a lot of decision-making in the cell’, says van Breukelen, so he and Pan monitored several of the numerous processes that regulate the activity of this key protein in the livers of the hibernating animals. Selecting five proteins that are known to regulate the p53 protein, Pan monitored the mRNA or protein levels for each of the regulatory proteins in the squirrel's liver and found that they were consistent with activation of the protein. ‘If a known positive regulator increased… then that should mean activation’, explains van Breukelen.

Pan and Michael Treat then investigated a whole slew of other cellular processes. They identified p53 in the nucleus of winter squirrels that were torpid and briefly aroused from hibernation, confirmed that p53 bound DNA in the nucleus (and could therefore presumably activate DNA transcription) and even showed that p53 could recruit RNA polymerase – which transcribes DNA into RNA – to genes. However, when Pan measured the mRNA levels in the torpid squirrels of genes that p53 is known to activate and initiate transcription of, she was amazed to see that instead of increasing the mRNA level of those genes, the expression levels were significantly reduced. Even though all of the other indicators suggested that p53 was active and would regulate transcription in the hibernating animals, it clearly was not. p53 is not an effective transcription factor in hibernating ground squirrels.

Explaining that he sees torpor as a mess, where imprecise regulation of cellular processes culminates in energetic savings, van Breukelen says, ‘The best way to make sure a machine doesn't use energy it not to slow it down, but rather to break it’, and this is how he sees the process in hibernation. However, he goes on to point out that the ‘mess’ must be repaired when an animal arouses from torpor, and he says, ‘I see the arousal process… as being where the fascinating biology happens.’

van Breukelen also warns that it would not have been possible to reveal this disruption to the transcription factor's activity in hibernation if they had focused only on one or two events in the cascade that leads to transcriptional activation. ‘It sounds simple, but investigators should not make assumptions about function based on other systems that are functioning in a different context’, he says, urging others to take a more holistic approach when attempting to untangle the complex network of events that regulate cellular physiology.