A novel slug-containing negative-feedback loop regulates SCF/c-Kit-mediated hematopoietic stem cell self-renewal

Leukemia. 2017 Feb;31(2):403-413. doi: 10.1038/leu.2016.201. Epub 2016 Jul 25.

Abstract

The stem cell factor (SCF)/c-Kit pathway has crucial roles in controlling hematopoietic stem cell (HSC) renewal. However, little is known about the intracellular regulation of the SCF/c-Kit pathway in HSCs. We report here that Slug, a zinc-finger transcription repressor, functions as a direct transcriptional repressor of c-Kit in HSCs. Conversely, SCF/c-Kit signaling positively regulates Slug through downstream c-Myc and FoxM1 transcription factors. Intriguingly, c-Kit expression is induced by SCF/c-Kit signaling in Slug-deficient HSCs. The balance between Slug and c-Kit is critical for maintaining HSC repopulating potential in vivo. Together, our studies demonstrate that Slug functions in a novel negative-feedback regulatory loop in the SCF/c-Kit signaling pathway in HSCs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cell Differentiation
  • Cell Self Renewal / genetics*
  • Cluster Analysis
  • Feedback, Physiological*
  • Forkhead Box Protein M1 / metabolism
  • Gene Expression
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Mice
  • Models, Biological
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins c-kit / genetics*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction
  • Snail Family Transcription Factors / metabolism*
  • Stem Cell Factor

Substances

  • Forkhead Box Protein M1
  • Proto-Oncogene Proteins c-myc
  • Snai1 protein, mouse
  • Snail Family Transcription Factors
  • Stem Cell Factor
  • Proto-Oncogene Proteins c-kit