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Cyclin-dependent kinase inhibitor p57KIP2 in soft tissue sarcomas and Wilms'tumors
I Orlow1, A Iavarone, S J Crider-Miller
1Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
Abstract:
Mammalian cyclin-dependent kinase inhibitors fall into two families, the INK4 and the CIP/KIP. The CIP/KIP family comprises three structurally related members, including p21CiP1/WAF1, p27KIP1, and p57KIP2. These proteins are all capable of inhibiting the progression of the cell cycle by binding and inhibiting G(1) cyclin/cyclin-dependent kinase complexes. In humans, p57KIP2 is expressed specifically in skeletal muscle, heart, brain, kidney, and lung. Human KIP2 resides in 11p15.5, a chromosomal region that is a common site for loss of heterozygosity in certain sarcomas, Wilms' tumors, and tumors associated with the Beckwith-Wiedemann syndrome. Because of the function, selective expression, and chromosomal location of p57KIP2, we undertook the present study to search for potential mutations of KIP2 in a cohort of 126 tumors composed of 75 soft tissue sarcomas and 51 Wilms' tumors. The KIP2 gene was characterized by Southern blot, comparative multiplex PCR, PCR -single-strand conformational polymorphism, and DNA sequencing assays in these neoplasms. Deletions of the KIP2 gene or point mutations at the region encoding the cyclin-dependent kinase inhibitory domain were not found in the tumors analyzed. The absence of KIP2 mutations might indicate that these tumors arise due to defects at a closely linked but separate locus. Alternatively, similarly to the mouse homologue, inactivation of KIP2 could occur via genomic imprinting.
Insights
Researchers found no mutations in the KIP2 gene in soft tissue sarcomas and Wilms' tumors. This suggests other genetic mechanisms, like genomic imprinting, may cause these cancers.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Mammalian cell cycle progression is regulated by cyclin-dependent kinase inhibitors, including the CIP/KIP family (p21CiP1/WAF1, p27KIP1, p57KIP2).
- The p57KIP2 protein inhibits G1 cyclin/cyclin-dependent kinase complexes, and its gene is located at chromosome 11p15.5, a region frequently altered in certain tumors.
- Human p57KIP2 exhibits specific expression in skeletal muscle, heart, brain, kidney, and lung.
Purpose of the Study:
- To investigate potential mutations in the KIP2 gene in soft tissue sarcomas and Wilms' tumors.
- To determine if KIP2 gene alterations contribute to the development of these specific neoplasms.
Main Methods:
- Analysis of 126 tumors (75 soft tissue sarcomas, 51 Wilms' tumors) for KIP2 gene alterations.
- Utilized Southern blot, comparative multiplex PCR, PCR-single-strand conformational polymorphism, and DNA sequencing.
Main Results:
- No deletions or point mutations within the cyclin-dependent kinase inhibitory domain of the KIP2 gene were detected in the analyzed tumor samples.
- The study did not find evidence of KIP2 gene mutations in soft tissue sarcomas or Wilms' tumors.
Conclusions:
- The absence of KIP2 mutations suggests that these tumors may arise from defects in a nearby but distinct genetic locus.
- Alternatively, KIP2 inactivation in these human tumors might occur through genomic imprinting, similar to its mouse homologue.