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PMID: 18292212 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Stem cells (Dayton, Ohio) ·Vol. 26 ·No. 5 ·2008-05-00 ·Pages 1253-64

Li N, Singh S, Cherukuri P, Li H, Yuan Z, Ellisen LW, Wang B, Robbins D, DiRenzo J

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.

MeSH Terms
Animals Cell Line Epithelial Cells/metabolism Female Gene Expression Regulation Hedgehog Proteins/genetics,metabolism Humans Kruppel-Like Transcription Factors/metabolism Mammary Glands, Animal/cytology,metabolism Mice Models, Biological Nerve Tissue Proteins/metabolism Phosphoproteins/genetics,metabolism Pregnancy Promoter Regions, Genetic/genetics Protein Binding Protein Isoforms/genetics,metabolism Signal Transduction Stem Cells/cytology,metabolism Trans-Activators/genetics,metabolism Transcription, Genetic Zinc Finger Protein Gli3
Chemicals
Gli3 protein, mouse Hedgehog Proteins Kruppel-Like Transcription Factors Nerve Tissue Proteins Phosphoproteins Protein Isoforms Trans-Activators Trp63 protein, mouse Zinc Finger Protein Gli3 ihh protein, mouse
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Li Na
Department of Pharmacology and Toxicology, Dartmouth Medical School, 7650 Remsen, Hanover, New Hampshire 03755, USA.
Singh Samer
Cherukuri Pratima
Li Hua
Yuan Ziqiang
Ellisen Leif W
Wang Baolin
Robbins David
DiRenzo James
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Article Info
Journal
Stem cells (Dayton, Ohio)
Abbr.
Stem Cells
ISSN
1549-4918
DOI
10.1634/stemcells.2007-0691
Published
2008-05-00
Epub
2008-00-21
Pages
1253-64
Language
English
Region
United States
NLM ID
9304532
PMCID
PMC3778935
Subset
IM
Grants
NCI NIH HHS · P30 CA023108 · United States
NCI NIH HHS · R01 CA108539 · United States
NIDCR NIH HHS · R01 DE015945 · United States
NCI NIH HHS · 5R01CA108539-04) · United States
External Links
PubMed source DOI: 10.1634/stemcells.2007-0691 PMC Full Text View journal details
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