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Negative regulation of c-abl tyrosine kinase by its variable N-terminal amino acids
1Department of Biology, University of California, San Diego, La Jolla, 92093.
Abstract:
Activation of the oncogenic potential of c-abl proto-oncogene has been correlated with the activation of its tyrosine kinase activity. The oncogenes derived from c-abl, e.g., gag/v-abl in Abelson murine leukemia virus or bcr/abl in chronic myelogenous leukemia, lack N-terminal coding sequences of the normal c-abl gene. In mouse and human cells, two sets of N-terminal amino acids encoded by 5'-variable exons are found in c-abl proteins. To assess the importance of N-terminal deletion in the activation of c-abl tyrosine kinase, a full length or an N-terminal deleted c-abl protein was expressed in bacteria and in monkey COS cells. Measurements of the autokinase activity of these two c-abl proteins showed that deletion of the N-terminal amino acids led to a three to five fold increase of the c-abl tyrosine kinase activity. Thus, the N-terminal deletion is important in the activation of c-abl proto-oncogene.
Insights
Deletion of N-terminal amino acids significantly increases the tyrosine kinase activity of the c-abl proto-oncogene. This finding highlights the role of N-terminal sequences in regulating oncogenic potential.
Area of Science:
- Molecular Biology
- Oncogenesis
- Biochemistry
Background:
- The c-abl proto-oncogene's oncogenic potential is linked to its tyrosine kinase activity.
- Oncogenes like gag/v-abl and bcr/abl, derived from c-abl, lack specific N-terminal coding sequences.
- Normal c-abl proteins contain N-terminal amino acids encoded by 5'-variable exons.
Purpose of the Study:
- To investigate the role of N-terminal deletion in the activation of c-abl tyrosine kinase activity.
- To determine the impact of removing N-terminal amino acids on the oncogenic potential of c-abl.
Main Methods:
- Expression of full-length and N-terminal deleted c-abl proteins in bacterial and monkey COS cells.
- Measurement of autokinase activity for both full-length and deleted c-abl proteins.
Main Results:
- Deletion of N-terminal amino acids resulted in a 3- to 5-fold increase in c-abl tyrosine kinase activity.
- The N-terminal region of c-abl appears to be a negative regulator of its kinase activity.
Conclusions:
- N-terminal deletion is a critical factor in the activation of c-abl proto-oncogene's tyrosine kinase.
- Understanding these regulatory mechanisms is crucial for targeting oncogenic pathways in diseases like chronic myelogenous leukemia.