New p57 KIP2 mutations in Beckwith-Wiedemann syndrome

Abstract

Beckwith-Wiedemann syndrome (BWS) is characterized by numerous growth abnormalities and an increased risk of childhood tumors. The gene for BWS is localized in the 11p15.5 region, as determined by linkage analysis of autosomal dominant pedigrees. The increased maternal transmission pattern seen in the autosomal dominant-type pedigrees and the findings of paternal uniparental disomy reported for a subgroup of patients indicate that the gene for BWS is imprinted. Previously, we found p57KIP2, which is a Cdk-kinase inhibitor located at 11p15, is mutated in two BWS patients. Here, we screened for the mutation of the gene in 15 BWS patients.

Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57 KIP2 requires binding to proliferating cell nuclear antigen

“…The finding that p57 has PCNA-binding activity at its C terminus whose disruption resulted in partial reduction of p57's ability to suppress cell transformation provides the first evidence that PCNA binding activity has a distinct role in p57's function. This finding is particularly noteworthy in light of recent reports that three of four p57 mutations identified in BWS patients retained only an intact N-terminal CDK-cyclin binding domain (11,12): one lost the central PAPA repeat and C-terminal domain, and two contained deletions of the PCNA binding domain (BWS8, and BWS204, Fig. 2 A).…”

“…Consistent with its suggested role in tumor growth suppression, mice lacking p57 function displayed altered cell proliferation and differentiation, increased apoptosis and phenotypes seen in patients with BWS (9, 10). More direct evidence for the involvement of the p57 gene in human cancer was obtained by the finding that four of 24 (17%) BWS patients examined contain mutations in the p57 gene that altered the structure of the p57 protein (11,12). Intriguingly, of the p57 mutations identified, three retained the N-terminal CDKcyclin binding domain: one lost the central PAPA repeat and C-terminal domain, and two contained deletions in the Cterminal QT domain.…”

p57KIP2 Modulates Stress-activated Signaling by Inhibiting c-Jun NH2-terminal Kinase/Stress-activated Protein Kinase

“…In humans, the p57 KIP2 gene is located in chromosome 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome, a familial cancer syndrome (5). Among patients with BeckwithWiedemann syndrome, several mutations in the p57 KIP2 gene have been detected that include deletions in the QT domain of p57 KIP2 (21,22). A deletion in the QT domain of p57 KIP2 may possibly help JNK/SAPK escape from negative regulation by p57 KIP2 .…”

Beckwith–Wiedemann syndrome

“…This is associated with mutations in CDKN1C or microdeletions of IC1 and very rarely IC2. 32,33,[35][36][37]40,44,45 Omphalocele. This is associated with an IC2 defect or CDKN1C mutation.…”