Modulation of immune responses by the tumor suppressor p53

Abstract

The commonly held view of the tumor suppressor p53 as a regulator of cell proliferation, apoptosis and senescence has expanded greatly in recent years to cover many biological processes as well as external and internal stress responses. Since the discovery over 30 years ago of p53 as a cellular protein that co-precipitates with the large T antigen of Simian Virus SV40, there has been an intertwining of p53 activities with immunerelated processes, especially as relates to cancer. A variety of interactions between the p53 and the immune stress systems are currently being addressed that suggest opportunities to utilize p53 in modulating immunological activities. Here, we discuss those interactions along with implications for human disease.

Introductory Chapter: Obesity—“OMICS” and Endocrinology

“…Suffice to mention here is that the involvement of Sirt1 in adipose tissue transformation is mediated by p53 transcriptional dysregulation, which causes repression of PPARγ and FOXO1, both being instrumental in the lipid metabolism of adipocytes [17][18][19][20]. Finally, Sirt1/p53 interactions may modulate the adipocytes' levels of adipocytokines, as well as immune responses, being important to maintain an abnormal adipose tissue-liver cross-talk leading to NAFLD in obesity [21][22][23][24][25][26][27][28][29].…”

“…The LPSs are dimeric polysaccharide moieties linked to a lipid core, anchored within the cell membrane [18,19], and have been shown to effect hepatic genomic stability [20] affecting reverse cholesterol transport (RCT) in macrophages by downregulation PPARγ [21][22][23][24][25][26][27][28][29][30]. LPSs have demonstrated to directly affect mitochondrial DNA synthesis linked to mitochondrial dysfunction [31].…”

“…A lowering of the ingestion of fat [35] suppresses plasma LPS levels, and has therefore become a strong tool in the reduction of both the development and impact of metabolic diseases on health in general. LPS has been shown to modulate SREBP expression in macrophages, while also subduing liver PGC1α expression [29,42,43], and thus being associated with an abnormal Sirt1-regulation of basal adipocyte cell functioning [27,44]. The LPS-facilitated "blockage" of the elimination of cholesterol from macrophages has been demonstrated to serve as an important factor in the cholesterol-rich lipoprotein intercommunication network [45][46][47], thus impacting on LPS neutralization in metabolic diseases, with focus on diabetes [48][49][50].…”

Evolution of Conformational Disorder & Diversity of the P53 Interactome

“…The P53 signalling protein The tumour suppressor p53 plays a central role in cancer suppression by preventing proliferation of damaged cells with potentially cancer-prone mutations through its ability to act as a DNA-binding protein and transcription factor, whereby it can induce the transactivation of proteins that play a role in cell cycle arrest, apoptosis, senescence, DNA repair or alter metabolism [20][21][22][23][24]. The p53 gene is p53 disorder and interactome one of the most widely mutated genes in human cancer, it can be observed in over 50% of all human tumours and these tumours respond poorly to therapy [25].…”

AATF Genome: Evolution of Allorecognition

“…Consequently, AATF has the potential to regulate several genes either through STAT3 or Akt 1. At this stage, it is pertinent to note that: a) IFN-γ has been shown to up-regulate the expression of genes coding for KLF4 and p53 [11,12] as well as down-regulate the c-myc gene transcription [13]; b) the tumor suppressor p53 has been found to up-regulate the expression of genes coding for KLF4 and MDM2 coupled with down-regulation of genes coding for C-myc, NFkB and IFN-γ [14][15][16][17][18]; c) the transcriptional factors E2F and C-myc were found induce the expression of genes coding for AATF [2,19] and polycomb group protein [20,21] Bmi-1 which, in turn, ensured sustained NFkB activation [22]; d) KLF4 was found to suppress SP1-dependent genes [19,21,23] coding for AATF, Bmi-1 and UCP2; e) C-myc has been shown to inhibit MDM2 protein through its ability to induce the expression of p19 ARF gene [24]. Taken together these findings precipitate the importance of AATF as the most crucial and critical cellcycle regulator as far was cell division is concerned.…”