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Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization
Johanna I. Partanen,
Anni I. Nieminen,
Tomi P. Mäkelä, and
Cancer Cell Circuitry Laboratory, Institute of Biomedicine/Biochemistry and Genome-Scale Biology Program, Biomedicum Helsinki, University of Helsinki, Room B231a, P.O Box 63, Haartmaninkatu 8, 00014, Helsinki, Finland
Edited by Joan S. Brugge, Harvard Medical School, Boston, MA, and approved July 31, 2007
Received for publication May 18, 2007.
Cellular organization into epithelial architecture maintainsstructural integrity and homeostasis by suppressing cell proliferationand apoptosis. However, it is unclear whether the epithelialorganization is sufficient to block induction of cell-autonomouscell cycle progression and apoptotic sensitivity by activatedoncogenes. We show that chronic activation of oncogenic c-Myc,starting in the developing 3D organotypic mammary acinar structures,results in hyperproliferation and transformed acinar morphology.Surprisingly, acute c-Myc activation in mature quiescent aciniwith established epithelial architecture fails to reinitiatethe cell cycle or transform these structures. c-Myc does reinitiatethe cell cycle in quiescent, but structurally unorganized, acini,which demonstrates that proper epithelial architecture is neededfor the proliferation blockade. The capability of c-Myc to reinitiatethe cell cycle in acinar structures is also restored by theloss of LKB1, a human homologue of the cell polarity proteinPAR4. The epithelial architecture also restrains the apoptoticactivity of c-Myc, but coactivation of c-Myc and a complementaryTNF-related apoptosis-inducing ligand death receptor pathwaycan induce a strong Bim and Bid-mediated apoptotic responsein the established acini. The results together expose surprisingproliferation and apoptosis resistance of organized epithelialstructures and identify a role for the polarity regulator LKB1in the development of c–Myc-resistant cell organization.
Key Words: 3D culture apoptosis
Author contributions: J.I.P. and J.K. designed research; J.I.P.and A.I.N. performed research; A.I.N. and T.P.M. contributednew reagents/analytic tools; J.I.P. and J.K. analyzed data;and J.I.P. and J.K. wrote the paper.