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.