HES and HERP families: Multiple effectors of the notch signaling pathway

Abstract

Notch signaling dictates cell fate and critically influences cell proliferation, differentiation, and apoptosis in metazoans. Multiple factors at each step-ligands, receptors, signal transducers and effectors-play critical roles in executing the pleiotropic effects of Notch signaling. Ligand-binding results in proteolytic cleavage of Notch receptors to release the signal-transducing Notch intracellular domain (NICD). NICD migrates into the nucleus and associates with the nuclear proteins of the RBP-Jk family (also known as CSL or CBF1/Su(H)/Lag-1). RBP-Jk, when complexed with NICD, acts as a transcriptional activator, and the RBP-Jk-NICD complex activates expression of primary target genes of Notch signaling such as the HES and enhancer of split [E(spl)] families. HES/E(spl) is a basic helixloop-helix (bHLH) type of transcriptional repressor, and suppresses expression of downstream target genes such as tissue-specific transcriptional activators. Thus, HES/E(spl) directly affects cell fate decisions as a primary Notch effector. HES/E(spl) had been the only known effector of Notch signaling until a recent discovery of a related but distinct bHLH protein family, termed HERP (HES-related repressor protein, also called Hey/Hesr/HRT/CHF/gridlock). In this review, we summarize the recent data supporting the idea of HERP being a new Notch effector, and provide an overview of the similarities and differences between HES and HERP in their biochemical properties as well as their tissue distribution. One key observation derived from identification of HERP is that HES and HERP form a heterodimer and cooperate for transcriptional repression. The identification of the HERP family as a Notch effector that cooperates with HES/E(spl) family has opened a new avenue to our understanding of the Notch signaling pathway.

The Notch signaling pathway: Transcriptional regulation at Notch target genes

“…The hairy/enhancer of split (Hes) genes are highly conserved proteins that are regulated by Notch in multiple cell types, reviewed in [7,8]. Hairy/Enhancer of split family genes were first described as neurogenic genes in Drosophila (like Notch, Deltex and Mastermind), since embryos lacking the function of these genes showed an increased number of neuroblasts at the expense of epidermal precursors, reviewed in [2,9].…”

“…Hairy/Enhancer of split family genes were first described as neurogenic genes in Drosophila (like Notch, Deltex and Mastermind), since embryos lacking the function of these genes showed an increased number of neuroblasts at the expense of epidermal precursors, reviewed in [2,9]. Several lines of evidence have suggested that these genes are indeed direct Notch target genes: a) The promoters of Hes1, Hes5 and Hes7 as well as Hey1, Hey2 and HeyL (subfamily of Hes, related with YRPW motif) can be activated by a constitutive active form of Notch1 [10 -12], reviewed in [7]; constitutive active Notch describes a mutant of Notch that is continuously proteolytically processed and migrating to the nucleus, b) endogenous Hey1 and Hey2 show an upregulation by NICD in several different cell lines [13], c) in co-culture experiments with Notch-ligand expressing cells, that achieve a more physiological level of Notch signaling, these genes are upregulated as well [13 -15]; these experiments were also performed in the presence of cyclohexamide, an inhibitor of protein synthesis, to exclude secondary effects, d) k-secretase inhibitor DAPT, which prevents cleavage of Notch, was added to Tcell leukemia cell lines which show constitutive-active Notch signaling; subsequent microarray analysis identified again members of this transcription factor family as direct Notch target genes [16]. Therefore, in mammals, the best-described Notch target genes are indeed the transcription factors Hes1, Hes5 and Hey1 [8,17].…”

“…Overexpression of Hes1 and Hes5 in bone marrow partly inhibits B-cell development [18]. Hes1 deficient mice are not viable and display multiple developmental defects, reviewed in [7]. CD25 (IL2-R and preTa, pre-T-cell receptor alphachain) were also shown to be Notch target genes in T-cells [19,20].…”

“…3A). Many proteins that mediate neuronal repression in Drosophila are encoded by the Enhancer of Split complex, reviewed in [7,119]. Therefore, Notch signaling seems to be an evolutionary conserved pathway for preventing equipotent cells from acquiring the same fate.…”

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…Meanwhile, the ANK domain weakly interacts with both CSL and a shorter sequence at the N‐terminal end of mastermind‐like 1 (MAML1) protein (the transcriptional co‐activator)21, 22. The formed transcription activation ternary complex NICD/CSL/MAML1 further upregulates the target genes (such as HES/HEY transcriptional repressors 23), which is known as the canonical Notch signaling pathway 3.…”