A role for atm in E-cadherin-mediated contact inhibition in epithelial cells.
Ataxia telangiectasia is a hereditary pleiomorphic syndrome caused by loss of Atm, a phosphoprotein involved in multiple signaling pathways. Here, we propose a novel role for atm in cultured epithelial cells, namely the regulation of cell growth by contact inhibition. We show that atm is upregulated in epithelial cells reaching confluence. Conditional expression of the PI 3-Kinase domain of atm in non-confluent Tac-2 epithelial cells increases the expression of the anti-proliferative gene Tis-21 and downregulates key cell cycle regulator genes, such as cyclins A, B1, B2, E and E2. Finally, we demonstrate that upregulation of atm, and thus Tis-21, in confluent Tac-2 cells can be inhibited by an E-cadherin antibody blocking specifically homophilic E-cadherin interactions between adjacent cell surfaces. Altogether, these results suggest that atm could participate in a molecular pathway linking extracellular signalling to cell cycle control and may help further clarify the role of Atm in epithelial cell biology and carcinogenesis.
Division of Oncology, Geneva Medical School, Geneva 4, Switzerland. genevieve.vaudan@hcuge.ch
Geneviève Vaudan
GV
Vutskits
Patrick
P
Salmon
Laurence
L
Mayor
Laszlo
L
Vutskits
Christophe
C
Cudré-Mauroux
Jesus
J
Soriano
Roberto
R
Montesano
Philippe
P
Maillet
André-Pascal
AP
Sappino
D000818:Animals; D001260:Ataxia Telangiectasia; D064007:Ataxia Telangiectasia Mutated Proteins; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003260:Contact Inhibition; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D064007:Ataxia Telangiectasia Mutated Proteins; D015820:Cadherins; D018797:Cell Cycle Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576325:Atm protein, mouse