Human p57, also designated Cyclin-dependent kinase inhibitor 1C or Kip2, is a 316-amino acid nuclear protein involved in regulation of cell proliferation. p57 is an inhibitor of cyclin-dependent kinases and is structurally related to other cyclin-dependent kinase as p21 (CIP1) and p27 (Kip1). It is also involved in apoptosis and differentiation. The CDKN1C gene, encoding p57, is located at chromosome 11 (11p15.5) and is genomic imprinted which means that only the maternal allele is expressed. Chromosomal rearrangement or abnormal DNA methylation of 11p15 have been associated with the Beckwith-Wiedemann syndrome – an overgrowth disorder characterized by increased risk of childhood cancer and certain congenital features (macrosomia and midline abdominal wall defects). p57 is involved in embryo- and organogenesis with varying spatial and temporal expression. In adult tissue, p57 is expressed in skeletal muscle, heart, lung, kidney, brain, pancreas and testis, while liver and spleen is negative. In normal placental tissue, nuclear staining for p57 is seen in cytotrophoblastic, intermediate trophoblastic, villous stromal cells and maternal decidua while syncytiotrophoblastic cells are negative.
Reduced expression of p57 compared to normal tissue is seen in a number of cancer types (bladder, breast, colorectal, lung and pancreatic). Additionally, expression of p57 in these tumour types was a positive prognostic marker.
P57 is useful in discrimination between complete and partial hydatidiform mole. Genotype of complete hydatidiform mole is diploid (46XX or 46XY) and since both p57 alleles are of paternal origin (and therefore both inactivated) complete hydatiform moles are p57 negative. Contrary, partial hydatiform moles are tri- (69XXY) or tetraploid (92XXXY) and have active maternal alleles and p57 expression. Several studies have confirmed the correlation between immunohistochemical expression of p57 and molecular genotyping.
Placenta is recommended as positive and negative tissue control. The protocol must be calibrated to give a moderate to strong nuclear staining reaction in the majority of cytotrophoblastic and intermediate trophoblastic cells, while an at least weak to moderate nuclear staining reaction must be seen in the majority of villous stromal cells. Decidua cells will show an intense nuclear staining reaction and cannot be used to calibrate the protocol or serve as a reliable internal positive tissue control due to high levels of p57 expression. No nuclear staining reaction must be seen in syncytiotrophoblastic cells.
Selected references
Westbury J, Watkins M, Ferguson-Smith AC, Smith J. Dynamic temporal and spatial regulation of the cdk inhibitor p57(kip2) during embryo morphogenesis. Mech Dev. 2001;109(1):83–9. Guo HUI, Tian TAO, Nan K, Wang W. p57: A multifunctional protein in cancer (Review). Int J Oncol. 2010;36(6):1321–1329. Kavanagh E, Joseph B. The hallmarks of CDKN1C (p57, KIP2) in cancer. Biochim Biophys Acta. 2011;1816(1):50–6. p57 immunohistochemistry and molecular genotyping. Mod Pathol. 2014;27(2):238–54.
24.06.14 - RR/LE