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sel-11 and cdc-42, two negative modulators of LIN-12/Notch activity in C. elegans
Min Sung Choi1, Andrew S Yoo, Iva Greenwald
1Department of Biological Sciences, Howard Hughes Medical Institute, Columbia University College of Physicians and Surgeons, New York, New York, United States of America.
Background:
LIN-12/Notch signaling is important for cell-cell interactions during development, and mutations resulting in constitutive LIN-12/Notch signaling can cause cancer. Loss of negative regulators of lin-12/Notch activity has the potential for influencing cell fate decisions during development and the genesis or aggressiveness of cancer.
Methodology/Principal Findings:
We describe two negative modulators of lin-12 activity in C. elegans. One gene, sel-11, was initially defined as a suppressor of a lin-12 hypomorphic allele; the other gene, cdc-42, is a well-studied Rho GTPase. Here, we show that SEL-11 corresponds to yeast Hrd1p and mammalian Synoviolin. We also show that cdc-42 has the genetic properties consistent with negative regulation of lin-12 activity during vulval precursor cell fate specification.
Conclusions/Significance:
Our results underscore the multiplicity of negative regulatory mechanisms that impact on lin-12/Notch activity and suggest novel mechanisms by which constitutive lin-12/Notch activity might be exacerbated in cancer.
Insights
Researchers identified two negative regulators of LIN-12/Notch signaling in C. elegans, SEL-11 and CDC-42. These findings reveal new mechanisms for controlling cell fate and offer insights into cancer development.
Area of Science:
- Developmental Biology
- Molecular Biology
- Cancer Research
Background:
- LIN-12/Notch signaling is crucial for cell-cell communication in development.
- Dysregulated LIN-12/Notch signaling, due to loss of negative regulators, is implicated in cancer genesis and progression.
Purpose of the Study:
- To identify and characterize negative modulators of LIN-12/Notch activity in C. elegans.
- To explore the role of these modulators in cell fate specification and their potential link to cancer.
Main Methods:
- Genetic screening in C. elegans to identify suppressors of lin-12 mutations.
- Characterization of the identified genes, sel-11 and cdc-42, using genetic and molecular approaches.
- Comparative analysis of SEL-11 with yeast Hrd1p and mammalian Synoviolin.
Main Results:
- Two negative regulators of lin-12 activity, sel-11 and cdc-42, were identified in C. elegans.
- SEL-11 was found to be homologous to yeast Hrd1p and mammalian Synoviolin.
- CDC-42 demonstrated genetic properties consistent with negative regulation of lin-12 during vulval precursor cell fate specification.
Conclusions:
- Multiple negative regulatory mechanisms control LIN-12/Notch pathway activity.
- These findings suggest novel pathways through which aberrant LIN-12/Notch signaling may contribute to cancer.
