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Genomic imprinting of p57KIP2, a cyclin-dependent kinase inhibitor, in mouse
Abstract:
p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin/Cdk complexes, and is a negative regulator of cell proliferation. The gene encoding human p57KIP is located on chromosome 11p15.5 (ref. 2), a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome, a familial cancer syndrome, marking it a tumour suppressor candidate. Several types of childhood tumours including Wilm's tumour, adrenocortical carcinoma and rhabdomyosarcoma display a specific loss of maternal 11p15 alleles, suggesting that genomic imprinting plays an important part. Genetic analysis of the Beckwith-Wiedemann syndrome has indicated maternal carriers as well as suggested a role in genomic imprinting. Here, as a first step towards elucidating the genesis of human cancers in this region, we showed that a mouse homologue of p57KIP2 is genomically imprinted. The paternally inherited allele is transcriptionally repressed and methylated. This murine gene maps to the distal region of chromosome 7, within a cluster of imprinted genes, including insulin-2, insulin-like growth factor-2, H19 and Mash2 (refs 14-18).
Insights
The p57KIP2 gene, a cell proliferation regulator, is genomically imprinted in mice. Its paternal allele is silenced and methylated, suggesting a role in tumor suppression and Beckwith-Wiedemann syndrome.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- p57KIP2 is a cell cycle inhibitor and tumor suppressor candidate.
- The human p57KIP2 gene is on chromosome 11p15.5, a region linked to cancers and Beckwith-Wiedemann syndrome.
- Loss of maternal 11p15 alleles in childhood tumors suggests genomic imprinting's role.
Purpose of the Study:
- To investigate genomic imprinting of the p57KIP2 gene in mice.
- To understand the genesis of human cancers in the 11p15.5 region.
Main Methods:
- Analysis of the mouse homologue of p57KIP2.
- Investigated gene imprinting patterns, including allele-specific expression and methylation.
Main Results:
- The mouse p57KIP2 gene is genomically imprinted.
- The paternally inherited allele is transcriptionally repressed.
- The repressed paternal allele is methylated.
- The murine gene maps to chromosome 7, near other imprinted genes.
Conclusions:
- Genomic imprinting of p57KIP2 is conserved in mice.
- Imprinting of p57KIP2 may contribute to its tumor suppressor function.
- Further research into imprinting in the 11p15.5 region is warranted for cancer studies.