The p57 protein, also known as CDKN1C, regulates cell growth and development. It acts like a brake inside cells, controlling when and how cells divide. This prevents unchecked cell proliferation. p57 contributes to maintaining normal cellular balance.
The Biological Role of p57
The p57 protein functions as a cyclin-dependent kinase inhibitor, often abbreviated as CDKI. It binds to and deactivates specific enzymes called cyclin-dependent kinases (CDKs), which are responsible for driving the cell cycle forward. By inhibiting CDKs, p57 effectively applies a “brake” to the cell’s progression through its growth and division phases, particularly the G1 phase. This action ensures that a cell only divides when the conditions are appropriate and necessary.
Beyond its direct interaction with CDKs, p57 also binds to proliferating cell nuclear antigen (PCNA), a protein involved in DNA replication. This additional binding halts DNA synthesis and prevents cells from entering the S phase of the cell cycle, where DNA is duplicated. By preventing excessive cell division, p57 suppresses tumor formation.
Genomic Imprinting and p57
A distinct feature of the gene that produces p57, CDKN1C, is its regulation through genomic imprinting. Genomic imprinting is a biological process where only one of the two inherited copies of a gene (from either parent) is active or “expressed.” The other copy is typically silenced, meaning it does not produce its corresponding protein. For CDKN1C, the copy inherited from the mother is usually active, producing p57, while the paternal copy is silenced.
This parent-of-origin specific expression is governed by DNA regions called imprinting centers. For CDKN1C, the KCNQ1OT1-DMR region regulates this imprinting. This region undergoes methylation, where chemical groups are added to the DNA, typically on the maternal allele, influencing gene activity. This epigenetic control helps maintain the correct p57 protein dosage, which is important during development.
Association with Genetic Syndromes
Disruptions in p57 function or expression can lead to several genetic conditions affecting growth and development. One such condition is Beckwith-Wiedemann syndrome (BWS), which is characterized by overgrowth. In individuals with BWS, mutations in the maternal CDKN1C gene or imprinting errors lead to reduced or absent functional p57 protein. This lack of p57’s growth-inhibiting function contributes to the syndrome’s characteristic signs, such as an enlarged tongue (macroglossia), overgrowth, and abdominal wall defects like omphalocele.
CDKN1C mutations are a frequent cause of familial BWS (approximately 40% of cases) and are also observed in a smaller percentage of sporadic cases (5-10%). Another rarer condition linked to CDKN1C is IMAGe syndrome, which presents with contrasting features of undergrowth. This syndrome is caused by specific maternally inherited mutations in the CDKN1C gene, particularly within its PCNA-binding domain. These mutations lead to a “gain-of-function” effect, resulting in increased p57 activity that impairs normal growth, leading to conditions like intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia, and genital anomalies.
Use in Clinical Diagnostics
The unique genetic regulation of p57 makes it a useful marker in clinical pathology, particularly for diagnosing certain pregnancy-related conditions. Immunohistochemical (IHC) staining for p57 is routinely used to help distinguish between different types of hydatidiform moles, also known as molar pregnancies. These are abnormal growths in the uterus that occur after fertilization, resulting from issues with parental genetic contribution.
In complete hydatidiform moles, the pregnancy tissue contains only paternal genetic material, meaning there is no maternal DNA contribution. Since the CDKN1C gene that produces p57 is paternally imprinted and maternally expressed, complete moles typically show an absence of p57 protein staining. In contrast, partial hydatidiform moles involve both maternal and paternal genetic contributions, leading to the presence of p57 protein staining. This clear difference in p57 staining patterns helps pathologists accurately classify molar pregnancies and distinguish them from non-molar or hydropic abortuses, which also show positive p57 staining. The accurate diagnosis is important for patient monitoring and management, as complete moles carry a higher risk of developing complications such as persistent gestational trophoblastic disease.