The influence of temperature may be giving an interesting working hypothesis for further research. What are the consequences if cancer cells are a different type of open system which also operates at a different temperature than a normal cell? Butler et al. have studied p53 and they argue that at temperatures above 37 degrees centigrades wild-type p53 spontaneously loses DNA binding activity. While folding kinetics do not show important changes in a range from 5 to 35 degrees C, the unfolding rates accelerate 10,000-fold. This leads to a somewhat unexpected mechanism of p53 inactivation. It could be the case that a fraction of p53 molecules become trapped in misfolded conformations with each folding-unfolding cycle due to the increased frequency of cycling. The occurrence of misfolded p53 proteins can lead to aggregation and subsequent ubiquitination in the cell, leading to p53 inactivation [648, 649] . If a key ''guardian of the genome integrity'' [650, 651] and its remarkable conformational flexibility [652] is challenged by an increase of temperature [653] , its role in genotoxic damage and adaptive response (like that of the skin to UVB damage [654] ) may be impaired. The same may occur for other members of the DNA damage response. An increment in temperature has already been linked to skin carcinogenesis. Boukamp et al. report in that [655] ''exposure of immortal human HaCaT skin keratinocytes (possessing UV-type p53 mutations) to 40 degrees C reproducibly resulted in tumorigenic conversion and tumorigenicity was stably maintained after recultivation of the tumors.''