Differential regulation of myc homologs by Wnt/β‐Catenin signaling in the early metazoan Hydra

Abstract

The c‐Myc protein is a transcription factor with oncogenic potential controlling fundamental cellular processes. Homologs of the human c‐ myc protooncogene have been identified in the early diploblastic cnidarian Hydra ( myc1 , myc2 ). The ancestral Myc1 and Myc2 proteins display the principal design and biochemical properties of their vertebrate derivatives, suggesting that important Myc functions arose very early in metazoan evolution. c‐Myc is part of a transcription factor network regulated by several upstream pathways implicated in oncogenesis and development. One of these signaling cascades is the Wnt/β‐Catenin pathway driving cell differentiation and developmental patterning, but also tumorigenic processes including aberrant transcriptional activation of c‐ myc in several human cancers. Here, we show that genetic or pharmacological stimulation of Wnt/β‐Catenin signaling in Hydra is accompanied by specific downregulation of myc1 at mRNA and protein levels. The myc1 and myc2 promoter regions contain consensus binding sites for the transcription factor Tcf, and Hydra Tcf binds to the regulatory regions of both promoters. The myc1 promoter is also specifically repressed in the presence of ectopic Hydra β‐Catenin/Tcf in avian cell culture. We propose that Hydra myc1 is a negative Wnt signaling target, in contrast to vertebrate c‐ myc , which is one of the best studied genes activated by this pathway. On the contrary, myc2 is not suppressed by ectopic β‐Catenin in Hydra and presumably represents the structural and functional c‐ myc ortholog. Our data implicate that the connection between β‐Catenin‐mediated signaling and myc1 and myc2 gene regulation is an ancestral metazoan feature. Its impact on decision making in Hydra interstitial stem cells is discussed.

c-Myc Upregulated by High Glucose Inhibits HaCaT Differentiation by S100A6 Transcriptional Activation

“…c-Myc is a transcription factor encompassing a helix-loop-helix structure that forms heterodimers with Max. c-Myc regulates a variety of fundamental cell biological processes including proliferation, apoptosis, differentiation, and metabolism ( 16 ). Firstly, the expression of c-Myc in HaCaT cells cultured in high glucose and keratinocytes at diabetic wound margin was observed.…”

Bacteria- and temperature-regulated peptides modulate β-catenin signaling in Hydra

“…Increased Wnt signaling causes the stem cells in Hydra to differentiate and to lose their potential to self-renew (61,62). Interestingly, the expression of both Eco peptides is regulated by the presence of Curvibacter, the main bacterial colonizer of Hydra, and low temperature.…”

“…Thereby, the opposing signaling outcomes of Wnt and Eco would determine the degree of differentiation in the tissue as increased Wnt signaling causes the differentiation of stem cells (61,62). This process is mediated by Myc1 in interstitial cells, which is directly affected by the increase of Wnt signals due to ALP treatment (62). Given that Eco peptides are able to counteract increased Wnt signals, we thus argue that the eco genes integrate environmental signals into the developmental program and thereby promote the stemness of the cells in the body column of Hydra.…”

“…In Hydra , the Wnt pathway is involved in head formation ( 36 ), control of bud formation ( 37 , 60 ), and the differentiation of stem cells ( 61 , 62 ). Most Wnt family members are expressed in the tip of the hypostome of Hydra ( 37 ), and the Wnt pathway has been shown to form the activating agent in the head organizer of Hydra ( 36 , 37 ).…”

“…Our model suggests that the ratio of recognized Wnt and Eco peptides by an individual cell determines the activation of Wnt-target genes. Thereby, the opposing signaling outcomes of Wnt and Eco would determine the degree of differentiation in the tissue as increased Wnt signaling causes the differentiation of stem cells ( 61 , 62 ). This process is mediated by Myc1 in interstitial cells, which is directly affected by the increase of Wnt signals due to ALP treatment ( 62 ).…”