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Farnesyltransferase activity and mRNA expression in human skin basal cell carcinomas
S G Khan1, R Dummer, J Siddiqui
1Department of Dermatology, Case Western Reserve University, Cleveland, Ohio 44106-5028, USA.
Abstract:
Ras oncogene encode a protein p2l which in its mutated form transforms mammalian cells only after membrane anchoring by a series of enzymatic reactions where the initial step is catalyzed by farnesyltransferase (FTase). For this reason, FTase has become an attractive target for the development of novel anticancer agents. Virtually nothing is known about FTase activity and the association between the expression of its alpha and beta subunit genes with respect to the processing of Ras p21 in human cancers. In this study, we found that compared to normal skin, FTase activity and levels of both cytosolic and membrane-bound Ha-Ras p21 were significantly higher in human skin basal cell carcinomas (BCCs). In addition, the expression of both alpha and beta subunit genes was significantly higher in BCCs than the normal skin. These results suggest an association between enhanced FTase activity and the processing of overexpressed Ras p21 in such tumor type. This may have a bearing on the pathogenesis of activated Ras oncogene containing human malignancies.
Insights
Farnesyltransferase (FTase) activity and Ras p21 processing are elevated in human skin basal cell carcinomas (BCCs). This suggests FTase may play a role in BCC development, offering a potential target for anticancer drug development.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Ras oncogenes encode proteins crucial for cell transformation.
- Membrane anchoring of Ras proteins, initiated by farnesyltransferase (FTase), is essential for their oncogenic function.
- FTase is a promising target for novel anticancer agent development.
Purpose of the Study:
- To investigate FTase activity in human skin basal cell carcinomas (BCCs).
- To examine the association between FTase subunit gene expression and Ras p21 processing in BCCs.
- To explore the role of FTase in the pathogenesis of Ras-driven malignancies.
Main Methods:
- Assay of FTase activity in BCCs and normal skin.
- Quantification of cytosolic and membrane-bound Ha-Ras p21 levels.
- Analysis of alpha and beta FTase subunit gene expression in BCCs.
Main Results:
- Significantly higher FTase activity was observed in BCCs compared to normal skin.
- Elevated levels of both cytosolic and membrane-bound Ha-Ras p21 were found in BCCs.
- Increased expression of both alpha and beta FTase subunit genes was detected in BCCs.
Conclusions:
- Enhanced FTase activity and Ras p21 processing are associated with human skin basal cell carcinomas.
- These findings suggest a potential role for FTase in the pathogenesis of BCCs.
- FTase represents a potential therapeutic target for cancers involving activated Ras oncogenes.