Understanding the non-canonical pathways involved in p53-mediated tumor suppression

Abstract

In the last three decades since the discovery of p53, it has become increasingly apparent that p53 plays a very important role in tumor suppression. Previously, it was thought that the tumor suppressive functions lied solely in the canonical p53-mediated apoptosis, cell cycle arrest and senescence. However, more recent research has shown that anti-oncogenic activity of p53 can still occur in the absence of these downstream functions. These results suggest that more non-canonical roles of p53 may have a much larger impact on other p53-regulated programs then initially anticipated. Recently, the non-canonical activities of p53 such as cell metabolism, autophagy and necrosis have been the subject of intense study. p53 affects many aspects of cellular metabolism including catabolism, anabolism and reactive oxygen species levels. p53 has a dual role in autophagy regulation. Initiation of autophagy occurs through direct transcription of pro-autophagy genes and inhibition transpires through a transcription-independent mechanism. The role of p53 in these cellular processes is quite complex and evidence suggests that p53 can play both a pro- and anti-oncogenic role in these non-conical pathways. Despite of more than 60,000 publications on p53 in the literature, the mechanisms for p53-mediated tumor suppression apparently needs to be further elucidated.

Fig. 1.

p53 effects multiple areas of cellular metabolism. p53 can repress the transcription of glucose transporters GLUT1 and GLUT4. TIGAR is upregulated by p53 to suppress glycolysis and divert the pathway into the pentose phosphate pathway. Not only does p53 effect glucose metabolism but also plays a role in mitochondrial respiration and ATP production via the upregulation of SCO2 and GLS2. SCO2 is essential for mediating the formation and stabilization of the COX complex and thus critical for oxidative phosphorylation. GLS2 is a protein that catalyzes glutamine into glutamate. Glutamate can then be converted to α-ketogluterate, a key component in the Krebs cycle.

Fig. 2.

p53 influences autophagy. p53 has a direct role in influencing autophagy directly and indirectly. p53 can directly upregulates pro-autophagic genes such as DRAM, which is involved in autophagy initiation. p53 also directly transcribes several genes involved in the IGF-1-AKT-mTOR pathways such as β1 and β2 subunits of AMPK, TSC2 and IGF-BP3. Upregulation of these genes leads to the eventual inhibition of mTOR and thus activation of autophagy. p53 also upregulates the Ulk1 kinase, which is involved in the initiation of autophagy.

Fig. 3.

Model. p53 regulates many cellular pathways, but the exact mechanistic role of p53 in tumor prevention has yet to be elucidated. There is increasing support for the idea that there may not be one downstream function of p53 that is solely responsible for preventing tumor formation, rather that there are multiple pathways that converge to exercise its tumor suppressive function.