Genomic imprinting of human p57KIP2 and its reduced expression in Wilms' tumors

Abstract

p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin complexes, and is a negative regulator of cell proliferation. The gene encoding human p57KIP2 is located on chromosome 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome (BWS), a cancer syndrome, making it a tumor suppressor candidate. Several types of childhood tumors including Wilms' tumor, adrenocortical carcinoma and rhabdomyosarcoma display a specific loss of maternal 11p15 alleles, suggesting that genomic imprinting plays an important part. Genetic analysis of the familial BWS has indicated maternal carriers and suggested a role in genomic imprinting. Previously, we demonstrated that p57KIP2 is imprinted in the mouse. Here we describe the genomic imprinting of human p57KIP2 and the reduction of its expression in Wilms' tumors. High resolution mapping locates p57KIP2 in the region responsible for both tumor suppressivity and BWS.

The cell cycle inhibitor p57Kip2 promotes cell death via the mitochondrial apoptotic pathway

“…7 Taken together, these observations suggest that that p57 Kip2 exerts tissue-specific effects during development. Interestingly during adulthood, it has also been reported that p57 Kip2 expression is reduced in various tumors, [8][9][10][11][12][20][21][22][23][24] suggesting a possible function for this protein in tumorigenesis. Importantly, decreased p57 Kip2 expression may provide an important prognostic implication for patients with ovarian, hepatocellular and colorectal cancers, and acute lymphoblastic leukemia.…”

Genomic imprinting and its relevance to genetic diseases

“…Although IGF2, H19, SNRPN and p57 ~P2 (Hatada et al, 1996a) were confirmed to be imprinted as are their mouse homologs, INS has been shown to be expressed biallelically. Searching around the SNRPN region identified 4 novel imprinted genes, ZNF127, PAR5, PAR1 and IPW (Sutcliffe et al, 1994;Wevrick et al, 1994), all expressing paternally.…”

Polymorphic and tissue-specific imprinting of the human wilms tumor gene,WT1

“…Nine imprinted genes have been identified in man: the insulin-like growth factor II gene (tGF2) (Ohlsson et a/., 1993;Giannoukakis et al, 1993) and its receptor gene (IGF2R) (Xu et al, 1993), H19 gene (H19) (Zang and Tycko, 1992), the p57 K~P2 gene (Hatada et al, 1996), the Wilms tumor suppressor gene (WT1) (Jinno et al, 1994), the small nuclear ribonucleoprotein-associated polypeptide N gene (SNRPN) (Oz~elik et al, 1993), and transcripts (IPW, PAR1 and PAR5) from the Prader-Willi syndrome critical region (Wevrick et al, 1994;Sutcliffe et al, 1994). Among them, IGF2, SNRPN, IPW, PARI and PAR5 are paternally expressed, and the remaining 3 are maternally expressed genes.…”