The cause(s) of adenoid cystic carcinoma is unknown to date, and risk factors for this form of cancer have not been proved consistently via scientific study. There is some indication that a tumor suppressor gene called p53 is inactivated in advanced and aggressive forms of adenoid cystic carcinoma. The p53 gene regulates cell division and hence restricts cell proliferation.
A risk factor is something that raises a person’s chances of getting cancer. Although risk factors frequently impact cancer development, the majority do not directly cause cancer. Some persons with several risk factors never get cancer, but others with no known risk factors do.
WHAT IS THE p53 gene?
It has a length of 393 amino acids (aa) with a calculated molecular weight of 44 kDa. It is a member of the p53 family that also consists of p63 and p73. Structurally, p53 is represented by an N-terminal transactivation domain, core DNA-binding and oligomerization domains, and a C-terminal regulatory domain. It is expected to exist as a homo-tetramer and displays approximately 72% and 76% aa identity with its mouse and rat orthologs, respectively. Mutations in the p53 gene are one of the most common genomic events associated with oncogenic transformation. Among its gene targets are a variety of components that promote DNA repair processes of apoptosis, such as cell cycle regulating proteins and Bcl-2 family members. p53 activities are closely managed by a network of protein-protein interactions, microRNAs, and a variety of post-translational modifications including phosphorylation, acetylation, methylation, and ubiquitination due to its important role in genomic homeostasis. Murine Double Minute 2 is a well-studied regulator (MDM2). MDM2 has been exhibited to inhibit p53 function by direct binding or as a Ubiquitin ligase (E3) that catalyzes p53 ubiquitination and proteasome-mediated destruction.
ROLE OF p53
The p53 protein functions as a transcription factor, positively or negatively regulating the expression of many responsive genes. It is involved in angiogenesis, cellular senescence, autophagy, cell survival, differentiation, and oxidative stress regulation. The p53 protein is found in the nucleus of cells all over the body, where it binds to DNA. When a cell’s DNA is damaged by agents such as harmful chemicals, radiation, or ultraviolet (UV) rays from sunlight, this protein plays a key role in deciding whether the DNA is repaired or the damaged cell self-destructs (undergo apoptosis). If the DNA is repairable, p53 turns on the other genes to fix it. But, if the DNA is unrepairable, this protein inhibits the cell from dividing and triggers apoptosis. p53 aids in the prevention of tumor growth by preventing cells with mutant or damaged DNA from proliferating. Extensive mutation searches revealed that over half of all human malignancies had a loss of function mutations in the p53 gene, indicating that p53 is a classic Knudson-type tumor suppressor.
Because p53 is necessary for DNA repair and cell division, it has been dubbed as the “guardian of the genome.”
MUTATION IN p53
Mutational inactivation is thought to be one of the most prevalent molecular pathways behind p53 dysfunction. Close examination of the mutation profiles indicated that the six amino acid residues Arg-175, Gly-245, Arg-248, Arg-249, Arg-273, and Arg-282 are the most commonly mutated in human malignancies. These mutations in p53’s DNA-binding domain impair its normal conformation, making mutant p53 deficient in sequence-specific transcriptional activation dependent on the wild-type p53-binding consensus element. Furthermore, mutant p53 has oncogenic potential and exhibits dominant-negative behavior toward wild-type p53 via the formation of a hetero-tetramer with wild-type p53.
Mutant p53 protein not only loses its primitive function of tumor suppression, but it may also gain the function of an oncogene, such as causing cellular over-proliferation and division, which causes cellular malignant transformation, tumor development, increased tumor invasion, and radiotherapy and chemotherapy resistance.
The p53 gene is located on chromosome 17. In the cell, the p53 protein attaches to DNA, prompting another gene to make p21, a protein that interacts with a cell division-promoting protein (cdk2). When p21 binds to cdk2, the cell is unable to progress to the next stage of cell division. Because mutant p53 can no longer bind DNA effectively, the p21 protein is no longer accessible to function as a ‘stop signal’ for cell division. As a result, cells divide uncontrollably and form tumors.
Increasing evidence suggests that certain cancer-derived mutant forms of p53 transactivate a variety of target genes, including MDR1, c-myc, proliferating cell nuclear antigen (PCNA), interleukin-6 (IL-6), insulin-like growth factor 1 (IGF-1), fibroblast growth factor (FGF), and epidermal growth factor receptor (EGFR). It is discovered that cancer-derived mutant p53 stimulates asparagine synthetase (ASNS) and telomerase reverse transcriptase (TERT). As a result, some cancer-derived p53 mutations are likely to transactivate growth-promoting and oncogenic genes, resulting in the development of aggressive cancers such as adenoid cystic carcinoma (ACC).
