P53 Gene as a Promising Biomarker and Potential Target for the Early Diagnosis of Reproductive Cancers

Abstract

One of the crucial aspects of cancer research is diagnosis with specificity and accuracy. Early cancer detection mostly helps make appropriate decisions regarding treatment and metastasis. The well-studied transcription factor tumor suppressor protein p53 is essential for maintaining genetic integrity. p53 is a key tumor suppressor that recognizes the carcinogenic biological pathways and eradicates them by apoptosis. A wide range of carcinomas, especially gynecological such as ovarian, cervical, and endometrial cancers, frequently undergo TP53 gene mutations. This study evaluates the potential of the p53 gene as a biological marker for the diagnosis of reproductive system neoplasms. Immunohistochemistry of p53 is rapid, easy to accomplish, cost-effective, and preferred by pathologists as a surrogate for the analysis of TP53 mutation. Thus, this review lays a groundwork for future efforts to develop techniques using p53 for the early diagnosis of cancer.

Keywords: biomarker; cancer; p53 gene; reproductive cancer; tumor suppressor gene.

Figure 1. Canonical functions of wild-type p53.

The functional properties of p53 are depicted in the figure. The p53 gene regulates a wide range of physiological functions, including immunological response, stem cell maintenance, cell metabolism, mitochondrial respiration, autophagy, angiogenesis, senescence, apoptosis, and fertility. It also delineates the regulatory mechanisms by which these activities are accomplished, including physical interactions with binding partners and transcriptional modification of target gene expression [8-16]. Image credit: Aswathi Ramachandran.

Figure 2. p53: a fencekeeper for cell growth and proliferation.

Many cellular stress cues trigger the activation of p53. p53 activators include hypoxia, oxidative stress, oncogene activation, nutritional stress, and DNA damage. Activation of p53 induces the transcriptional upregulation of one or more target genes, which mediate the biological consequences depicted in the figure, and lead to cell cycle arrest at the G1/S or G2/M checkpoints [17-21]. ARF = alternative reading frame (tumor suppressor protein); MDM2 = murine double minute 2; MDMX = murine double minute X; ATM = ataxia telangiectasia mutated; ATR = ATM-related; PCNA = proliferating cell nuclear antigen; GADD45 = growth arrest and DNA damage-inducible 45; cdc = cell division cycle 25C; Rb = retinoblastoma protein; P = phosphate; E2F = eukaryotic transcription factors; CDK = cyclin-dependent kinase; ┴ = inhibit; ↓= activating Image credit: Aswathi Ramachandran.

Figure 3. The autoregulatory feedback loop between MDM2 and p53.

An abundance of correlative details indicates that the primary mechanism of p53 regulation in both normal and stressful circumstances is the p53-MDM2 autoregulatory loop. This diagram showed how MDM2 emerged as p53’s primary negative regulator. As MDM2 is a transcriptional target of p53, a negative feedback loop is created. Following the stabilization of the damage, active p53 attaches to the MDM2 P2 promoter and stimulates transcription of the gene. MDM2, in turn, disables p53 via one of the three mechanisms [22-25]. ARF = alternative reading frame (tumor suppressor protein); MDM2 = murine double minute 2; MDMX = murine double minute X; TAD = transactivation domains; UB = ubiquitin Image credit: Aswathi Ramachandran.