p21^WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation

Abstract

In keratinocytes, the cyclin/CDK inhibitor p21 WAF1/Cip1 is a direct transcriptional target of Notch1 activation; loss of either the p21 or Notch1 genes expands stem cell populations and facilitates tumor development. The Notch1 tumor-suppressor function was associated with down-regulation of Wnt signaling. Here, we show that suppression of Wnt signaling by Notch1 activation is mediated, at least in part, by down-modulation of Wnts gene expression. p21 is a negative regulator of Wnts transcription downstream of Notch1 activation, independently of effects on the cell cycle. More specifically, expression of the Wnt4 gene is under negative control of endogenous p21 both in vitro and in vivo. p21 associates with the E2F-1 transcription factor at the Wnt4 promoter and causes curtailed recruitment of c-Myc and p300, and histone hypoacetylation at this promoter. Thus, p21 acts as a selective negative regulator of transcription and links the Notch and Wnt signaling pathways in keratinocyte growth control.[Keywords: Differentiation; stem cell potential; transcription; chromatin; E2F-1; c-Myc; p300] Supplemental material is available at http://www.genesdev.org.

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

“…Inhibition of Notch signaling increases the expression of Wnt ligands, leading to increased Wnt signaling (59). Consistent with this, loss-of-function mutations in Notch1 in head and neck squamous cell carcinoma cell lines sensitize them to PORCN inhibitors (34).…”

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

“…Loss of Notch1 signaling seems to activate beta‐catenin signaling in human CSCC 28, which can be repressed by the introduction of a dominant active form of NOTCH130. In particular, p21 (a downstream mediator of Notch1‐induced growth arrest as we described above) also contributes to the downregulation of Wnt signaling, which likely account for the decreased levels of beta‐catenin activation by activated NOTCH134. Furthermore, a negative feedback loop involving p63 is thought to modulate this pathway in keratinocytes.…”

KLF4, p21 and context-dependent opposing forces in cancer

“…This might be another function of p21 that is unrelated to its role as a CDK inhibitor. In this setting, p21 bound to the promoter of Wnt genes and repressed their transcription through a process that might involve association with the E2F1 transcription factor 126 . Interestingly, E2F1 and other members of the E2f family have ambiguous functions in cancer (TABLE 2).…”