The protein p73 was first identified as a relative of the extensively studied p53 protein. Its discovery sparked interest due to structural similarities to p53, a well-known tumor suppressor. Despite this resemblance, p73 possesses distinct and significant functions that extend beyond p53, playing diverse roles in the body’s fundamental processes.
Understanding the p73 Gene and Protein
P73 is a protein encoded by the TP73 gene, located on chromosome 1p36.2-3 in humans. This gene is classified as a transcription factor, meaning its primary role involves regulating the activity of other genes by controlling when and how they are expressed. P73 belongs to a family of proteins that includes p53 and p63, all recognized for their involvement in maintaining cellular stability and regulation.
P73 exists in various forms, known as isoforms. These isoforms arise from different starting points in the gene sequence and alternative splicing of the RNA, leading to proteins with distinct N-terminal (beginning) and C-terminal (end) regions. These structural variations influence the protein’s function, allowing p73 to participate in a wide array of cellular processes. For instance, isoforms with a transactivation domain (TAp73) can activate gene expression, while those lacking this domain (ΔNp73) inhibit it.
p73’s Diverse Functions in the Body
Beyond its implications in disease, p73 plays diverse roles in normal physiological processes. Its involvement begins early in development, where it contributes to the formation of various structures. For example, p73 is involved in neural tube closure and overall brain development.
P73 also holds importance in neurogenesis, the process of forming new neurons, both during embryonic stages and in the adult brain. It helps maintain the pool of neural stem cells by promoting their self-renewal and proliferation, while also preventing their premature aging. Certain p73 isoforms are involved in maintaining the health and survival of mature neurons. In addition to its neurological roles, p73 contributes to fertility and reproductive functions, including spermatogenesis in males.
The Complex Role of p73 in Cancer
The involvement of p73 in cancer is intricate, exhibiting a dual nature where it can either suppress or promote tumor growth. Some isoforms of p73, specifically those containing a transactivation domain (TAp73), can act as tumor suppressors. These isoforms induce cellular responses such as programmed cell death (apoptosis) or halting cell division, similar to p53, in response to cellular damage. This function helps eliminate abnormal cells.
Conversely, other p73 isoforms, particularly the N-terminally truncated forms (ΔNp73), can promote tumor survival and growth. These pro-oncogenic isoforms can counteract the tumor-suppressing activities of TAp73 or even p53 itself. While p73 is rarely mutated in human cancers, its expression levels and the balance between its different isoforms are frequently disrupted. This dysregulation can contribute to cancer progression by promoting an immunosuppressive environment within the tumor or influencing processes like angiogenesis, the formation of new blood vessels that feed tumors.
How p73 Differs from p53
Despite their shared ancestry and some functional overlaps, p73 and p53 exhibit distinct characteristics. A primary difference lies in their mutation patterns in cancer; p53 is frequently mutated in over half of all human cancers, often leading to a loss of its tumor suppressor function. In contrast, the TP73 gene is rarely mutated in human cancers, although its expression levels are often altered.
Another key distinction is p73’s diverse roles in normal physiological processes, such as embryonic development and neurogenesis. While p53 is primarily known as the “guardian of the genome” due to its role in DNA damage response and tumor suppression, p73’s functions extend more broadly into developmental pathways and the maintenance of neuronal health. P73 is characterized by the presence of both tumor-suppressive (pro-apoptotic) and pro-survival (oncogenic) isoforms, which is a less pronounced feature of p53. These distinct isoforms allow p73 to fine-tune cellular responses, contributing to its complex and varied roles in both healthy tissues and disease states.