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Deregulated expression of cell-cycle proteins during premalignant progression in SENCAR mouse skin
M L Rodriguez-Puebla1, M LaCava, I B Gimenez-Conti
1The University of Texas MD Anderson Cancer Center, Science Park-Research Division, Smithville 78957, USA.
Abstract:
It is now evident that several genes encoding regulatory activities that control the mammalian cell cycle, particularly some that control the progression of quiescent cells through G1 and into S phase, are targets for alterations that underlie the development of neoplasms. Here, we made a sequential study of alterations in cell cycle protein expression and complex formation among cyclin, cyclin dependent kinases (CDKs) and CDK inhibitors (CKIs) during premalignant progression in SENCAR mouse skin tumors. Changes in the level of expression were observed in positive (cyclin D1, D2, and E2F family members) and negative regulators (p16Ink4a, p57Kip2) of the cell cycle. Also, we observed the formation of cyclin/CDK/CKI complexes. The amounts of these proteins and complexes increased substantially at specific times during promotion but not during malignant conversion to carcinomas. These data show that deregulation of growth control occurs in benign tumors and that subsequent mutations not involved cell-cycle regulation are probably necessary to induce invasive behavior.
Insights
Cell cycle regulators are altered in benign skin tumors, indicating early growth control deregulation. Invasive behavior likely requires mutations beyond cell cycle control.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Cell cycle regulation is crucial for preventing neoplasms.
- Alterations in cell cycle genes are implicated in cancer development.
- Understanding these changes during tumor progression is key.
Purpose of the Study:
- To investigate sequential alterations in cell cycle proteins and complexes during premalignant skin tumor progression.
- To identify changes in positive and negative cell cycle regulators and their complexes.
- To determine if these changes correlate with benign tumor promotion or malignant conversion.
Main Methods:
- Sequential analysis of SENCAR mouse skin tumors.
- Studied expression levels of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (CKIs).
- Examined the formation of cyclin/CDK/CKI complexes.
Main Results:
- Observed changes in expression of positive regulators (cyclin D1, D2, E2F) and negative regulators (p16Ink4a, p57Kip2).
- Detected the formation of cyclin/CDK/CKI complexes.
- Protein and complex levels increased during tumor promotion but not malignant conversion.
Conclusions:
- Deregulation of cell cycle control occurs early in benign tumor development.
- Benign tumors exhibit altered growth control mechanisms.
- Invasive behavior likely necessitates mutations independent of cell cycle regulation.