Reciprocal intraepithelial interactions between TP63 and hedgehog signaling regulate quiescence and activation of progenitor elaboration by mammary stem cells. Academic Article uri icon

Overview

MeSH

  • Animals
  • Cell Line
  • Female
  • Gene Expression Regulation
  • Humans
  • Kruppel-Like Transcription Factors
  • Mice
  • Models, Biological
  • Nerve Tissue Proteins
  • Pregnancy
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Isoforms
  • Transcription, Genetic

MeSH Major

  • Epithelial Cells
  • Hedgehog Proteins
  • Mammary Glands, Animal
  • Phosphoproteins
  • Signal Transduction
  • Stem Cells
  • Trans-Activators

abstract

  • TP63 is required for preservation of epithelial regenerative stasis and regulates the activity of diverse genetic pathways; however, specific effector pathways are poorly understood. Data presented here indicate that reciprocal regulatory interactions between hedgehog signaling and TP63 mediate stage-specific effects on proliferation and clonigenicity of separable enriched mammary stem and progenitor fractions. Analysis of DeltaN-p63 and TA-p63 indicates segregated expression in mammary stem and progenitor fractions, respectively, demonstrating that differential TP63 promoter selection occurs during elaboration of mammary progenitors by mammary stem cells. This segregation underlies mammary progenitor-specific expression of Indian Hedgehog, identifying it as a binary transcriptional target of TP63. Hedgehog activation in vivo enhances elaboration of mammary progenitors and decreases label retention within mammary stem cell-enriched fractions, suggesting that hedgehog exerts a mitogenic effect on mammary stem cells. Hedgehog signaling promotes differential TP63 promoter usage via disruption of Gli3 or Gli3(R) accumulation, and shRNA-mediated disruption of Gli3 expression was sufficient to alter TP63 promoter usage and enhance clonigenicity of mammary stem cells. Finally, hedgehog signaling is enhanced during pregnancy, where it contributes to expansion of the mammary progenitor compartment. These studies support a model in which hedgehog activates elaboration and differentiation of mammary progenitors via differential TP63 promoter selection and forfeiture of self-renewing capacity.

publication date

  • May 2008

has subject area

  • Animals
  • Cell Line
  • Epithelial Cells
  • Female
  • Gene Expression Regulation
  • Hedgehog Proteins
  • Humans
  • Kruppel-Like Transcription Factors
  • Mammary Glands, Animal
  • Mice
  • Models, Biological
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Pregnancy
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Isoforms
  • Signal Transduction
  • Stem Cells
  • Trans-Activators
  • Transcription, Genetic

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3778935

Digital Object Identifier (DOI)

  • 10.1634/stemcells.2007-0691

PubMed ID

  • 18292212

Additional Document Info

start page

  • 1253

end page

  • 1264

volume

  • 26

number

  • 5