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PMID: 12944493 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The intracellular form of notch blocks transforming growth factor beta-mediated growth arrest in Mv1Lu epithelial cells.

Molecular and cellular biology ·Vol. 23 ·No. 18 ·2003-09-00 ·Pages 6694-701

Rao P, Kadesch T

Abstract

Notch signaling influences a variety of cell fate decisions during development, and constitutive activation of the pathway can provoke unbridled cell growth and cancer. The mechanisms by which Notch affects cell growth are not well established. We describe here a novel link between Notch and cell cycle control. We found that Mv1Lu epithelial cells harboring an oncogenic form of Notch (NICD) are resistant to the cell cycle-inhibitory effects of transforming growth factor beta (TGF-beta). NICD did not affect TGF-beta signaling per se but blocked induction of the Cdk inhibitor p15(INK4B). c-Myc, whose down-regulation by TGF-beta is required for p15(INK4B) induction, remained elevated in the NICD-expressing cells. c-Myc expression was also maintained in low serum, indicating that Notch's effects on c-Myc are not specific to TGF-beta. Our results are consistent with a model in which a strong Notch signal indirectly deregulates c-Myc expression and thereby renders Mv1Lu epithelial cells resistant to growth-inhibitory signals.

MeSH Terms
Animals Cell Cycle Proteins/genetics,metabolism Cell Division/drug effects,physiology Cell Line Cyclin-Dependent Kinase Inhibitor p15 Cyclin-Dependent Kinase Inhibitor p16/genetics,metabolism Epithelial Cells/cytology,drug effects,physiology Gene Expression Regulation Genes, myc Membrane Proteins/genetics,metabolism Protein Structure, Tertiary Receptors, Notch Signal Transduction Transduction, Genetic Transforming Growth Factor beta/metabolism,pharmacology Tumor Suppressor Proteins
Chemicals
Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p15 Cyclin-Dependent Kinase Inhibitor p16 Membrane Proteins Receptors, Notch Transforming Growth Factor beta Tumor Suppressor Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Rao Prakash
Department of Genetics, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104-6145, USA.
Kadesch Tom
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.18.6694-6701.2003
Published
2003-09-00
Pages
6694-701
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC193715
Subset
IM
Grants
NCI NIH HHS · CA 09140 · United States
NCI NIH HHS · T32 CA009140 · United States
NIGMS NIH HHS · R01 GM 58228 · United States
NIGMS NIH HHS · T32 GM008216 · United States
NIGMS NIH HHS · T32 GM 08216 · United States
External Links
PubMed source DOI: 10.1128/MCB.23.18.6694-6701.2003 PMC Full Text View journal details
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