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PMID: 14993595 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 10 ·2004-03-09 ·Pages 3438-43

Mills KR, Reginato M, Debnath J, Queenan B, Brugge JS

Abstract

The molecular events regulating the elimination of cells to create a hollow lumen during tissue development are poorly understood. By using an in vitro morphogenesis model in which MCF-10A human mammary epithelial cells form hollow acini-like structures, we have observed both caspase-mediated apoptosis and autophagy associated with cells that are lost during lumen formation. Here, we show that the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates induction of autophagic processes associated with lumen formation. TRAIL is up-regulated during morphogenesis of MCF-10A mammary epithelial cells in 3D basement-membrane cultures and inhibition of TRAIL signaling during morphogenesis blocks the formation of autophagic vacuoles. In addition, treatment with exogenous TRAIL induces extensive autophagy in monolayer and 3D cultures. When combined with inhibition of caspase 3 activity (by Bcl-X(L) overexpression), inhibition of TRAIL-induced autophagy results in luminal filling. Thus, TRAIL regulates an autophagic program during acinar morphogenesis, which together with caspase-mediated apoptotic events, results in lumen formation during MCF-10A morphogenesis.

MeSH Terms
Apoptosis/physiology Apoptosis Regulatory Proteins Autophagy/physiology Breast/cytology,growth & development,physiology Cell Line Epithelial Cells/cytology,physiology Female Humans In Vitro Techniques Membrane Glycoproteins/physiology Morphogenesis Signal Transduction TNF-Related Apoptosis-Inducing Ligand Tumor Necrosis Factor-alpha/physiology
Chemicals
Apoptosis Regulatory Proteins Membrane Glycoproteins TNF-Related Apoptosis-Inducing Ligand TNFSF10 protein, human Tumor Necrosis Factor-alpha
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Mills Kenna R
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Reginato Mauricio
Debnath Jayanta
Queenan Bridget
Brugge Joan S
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0400443101
Published
2004-03-09
Epub
2004-00-01
Pages
3438-43
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC373480
Subset
IM
Grants
NCI NIH HHS · P01 CA080111 · United States
NCI NIH HHS · 1KO8CA098419 · United States
NCI NIH HHS · P50 CA089393 · United States
NCI NIH HHS · CA105134 · United States
NCI NIH HHS · CA80111 · United States
NCI NIH HHS · R01 CA105134 · United States
NCI NIH HHS · K08 CA098419 · United States
NCI NIH HHS · CA89393 · United States
External Links
PubMed source DOI: 10.1073/pnas.0400443101 PMC Full Text View journal details
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