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Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo
A I Robles1, M L Rodriguez-Puebla, A B Glick
1The University of Texas, M.D. Anderson Cancer Center, Science Park-Research Division (SPRD), Smithville, Texas 78957 USA.
Abstract:
Cyclin D1 is part of a cell cycle control node consistently deregulated in most human cancers. However, studies with cyclin D1-null mice indicate that it is dispensable for normal mouse development as well as cell growth in culture. Here, we provide evidence that ras-mediated tumorigenesis depends on signaling pathways that act preferentially through cyclin D1. Cyclin D1 expression and the activity of its associated kinase are up-regulated in keratinocytes in response to oncogenic ras. Furthermore, cyclin D1 deficiency results in up to an 80% decrease in the development of squamous tumors generated through either grafting of retroviral ras-transduced keratinocytes, phorbol ester treatment of ras transgenic mice, or two-stage carcinogenesis.
Insights
Cyclin D1, a cell cycle regulator, is crucial for ras-mediated cancer development. Its absence significantly reduces tumor formation in mice, highlighting its role in oncogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Cell Cycle Regulation
Background:
- Cyclin D1 is a key regulator of the cell cycle, frequently deregulated in human cancers.
- Despite its prevalence in cancer, cyclin D1 appears dispensable for normal mouse development and cell culture growth.
Purpose of the Study:
- To investigate the specific role of cyclin D1 in ras-mediated tumorigenesis.
- To determine if cyclin D1 is essential for the development of squamous cell tumors initiated by oncogenic ras.
Main Methods:
- Analyzing cyclin D1 expression and kinase activity in keratinocytes stimulated by oncogenic ras.
- Evaluating tumor development in cyclin D1-deficient mice subjected to various chemical and genetic carcinogenesis models.
Main Results:
- Oncogenic ras up-regulates cyclin D1 expression and associated kinase activity in keratinocytes.
- Cyclin D1 deficiency led to an 80% reduction in squamous tumor formation across different experimental models.
Conclusions:
- Ras-mediated tumorigenesis is dependent on signaling pathways that preferentially utilize cyclin D1.
- Cyclin D1 is essential for the development of ras-induced squamous cell tumors, suggesting it as a potential therapeutic target.