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Preferential alternative splicing in cancer generates a K-sam messenger RNA with higher transforming activity
H Itoh1, Y Hattori, H Sakamoto
1Genetics Division, National Cancer Center Research Institute, Tokyo, Japan.
Abstract:
K-sam, also designated fibroblast growth factor receptor 2/BEK, was originally cloned from a stomach cancer cell line KATO-III. The gene is amplified and overexpressed preferentially in poorly differentiated types of stomach cancers. The major K-sam transcript in KATO-III cells encodes a receptor protein with a truncated carboxyl terminus and with a high-affinity binding site for keratinocyte growth factor. This truncated type is produced by an alternative splicing mechanism, and in normal tissues, the truncated type is far less prevalent than the untruncated form. The variant K-sam complementary DNA lacks tyrosine 769, which is a putative phospholipase C gamma 1 association site, and showed a higher transforming activity to NIH3T3 cells than the untruncated form, which is identical with the keratinocyte growth factor receptor.
Insights
K-SAM, a fibroblast growth factor receptor 2/BEK, is amplified in stomach cancer. A truncated K-SAM variant, prevalent in cancer cells, exhibits higher transforming activity due to alternative splicing.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- K-SAM (fibroblast growth factor receptor 2/BEK) is identified in KATO-III stomach cancer cells.
- Gene amplification and overexpression of K-SAM are observed in poorly differentiated stomach cancers.
Purpose of the Study:
- To investigate the role of K-SAM in stomach cancer development.
- To characterize the K-SAM transcript variants and their functional significance.
Main Methods:
- Cloning of K-SAM from KATO-III cells.
- Analysis of K-SAM transcript variants using complementary DNA (cDNA).
- Assessment of transforming activity in NIH3T3 cells.
Main Results:
- A major K-SAM transcript in KATO-III cells encodes a truncated receptor with high affinity for keratinocyte growth factor.
- This truncated variant is produced via alternative splicing and is less common in normal tissues.
- The variant complementary DNA (cDNA) lacks tyrosine 769, a phospholipase C gamma 1 association site.
- The truncated K-SAM variant demonstrates higher transforming activity compared to the untruncated form.
Conclusions:
- Alternative splicing generates a truncated K-SAM variant with increased transforming potential in stomach cancer.
- This truncated K-SAM may play a significant role in the pathogenesis of poorly differentiated stomach cancers.