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Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function
Indranil Das1, Colleen Craig, Yasuhiro Funahashi
1Department of Pathology and Obstetrics/Gynecology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
The Journal of Biological Chemistry
|May 5, 2004
Summary
Aberrant Notch signaling drives cancer. Gamma-secretase/presenilin inhibitors block Notch4/int-3 oncoprotein activity by preventing cell surface cleavage, but not TAN-1 oncoprotein activity, due to differing protein structures.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Notch receptor signaling is crucial for cell fate determination during development.
- Truncated Notch oncoproteins, such as Notch4/int-3 and TAN-1, can lead to uncontrolled cell growth.
- The role of gamma-secretase/presenilin activity in the processing of Notch oncoproteins was previously unknown.
Purpose of the Study:
- To investigate the dependence of Notch4/int-3 and TAN-1 oncoproteins on gamma-secretase/presenilin activity.
- To determine the impact of inhibiting gamma-secretase/presenilin on Notch oncoprotein function and cellular responses.
- To explore the therapeutic potential of gamma-secretase/presenilin inhibitors in Notch-related cancers.
Main Methods:
- Utilized cell lines deficient in presenilins or treated with gamma-secretase/presenilin inhibitors.
- Examined the activation of the downstream transcription factor CSL.
- Assessed the cellular localization of Notch oncoproteins under inhibited gamma-secretase/presenilin activity.
Main Results:
- Gamma-secretase/presenilin inhibition abrogated Notch4/int-3-induced CSL activation.
- Both Notch4/int-3 and TAN-1 accumulated at the cell surface upon gamma-secretase/presenilin inhibition.
- Gamma-secretase/presenilin inhibition blocked cellular responses to Notch4/int-3 but not TAN-1.
- TAN-1's independence from gamma-secretase/presenilin was attributed to some variants lacking transmembrane domains.
Conclusions:
- Notch4/int-3 oncoprotein activity is dependent on gamma-secretase/presenilin-mediated cleavage.
- TAN-1 oncoprotein activity can be independent of gamma-secretase/presenilin due to structural variations.
- Gamma-secretase/presenilin inhibitors show potential for treating Notch4/int-3-driven neoplasms but have limitations for TAN-1-driven cancers.