Partanen Johanna I, Nieminen Anni I, Mäkelä Tomi P, Klefstrom Juha
Cancer Cell Circuitry Laboratory, Institute of Biomedicine/Biochemistry and Genome-Scale Biology Program, Biomedicum Helsinki, University of Helsinki, Room B231a, PO Box 63, Haartmaninkatu 8, 00014, Helsinki, Finland.
Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14694-9. doi: 10.1073/pnas.0704677104. Epub 2007 Aug 31.
Cellular organization into epithelial architecture maintains structural integrity and homeostasis by suppressing cell proliferation and apoptosis. However, it is unclear whether the epithelial organization is sufficient to block induction of cell-autonomous cell cycle progression and apoptotic sensitivity by activated oncogenes. 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 acini with established epithelial architecture fails to reinitiate the cell cycle or transform these structures. c-Myc does reinitiate the cell cycle in quiescent, but structurally unorganized, acini, which demonstrates that proper epithelial architecture is needed for the proliferation blockade. The capability of c-Myc to reinitiate the cell cycle in acinar structures is also restored by the loss of LKB1, a human homologue of the cell polarity protein PAR4. The epithelial architecture also restrains the apoptotic activity of c-Myc, but coactivation of c-Myc and a complementary TNF-related apoptosis-inducing ligand death receptor pathway can induce a strong Bim and Bid-mediated apoptotic response in the established acini. The results together expose surprising proliferation and apoptosis resistance of organized epithelial structures and identify a role for the polarity regulator LKB1 in the development of c-Myc-resistant cell organization.
细胞组织形成上皮结构通过抑制细胞增殖和凋亡来维持结构完整性和内环境稳定。然而，尚不清楚上皮组织是否足以阻止激活的癌基因诱导细胞自主的细胞周期进程和凋亡敏感性。我们发现，致癌性c-Myc的慢性激活，始于发育中的三维器官型乳腺腺泡结构，会导致过度增殖和腺泡形态转变。令人惊讶的是，在具有成熟上皮结构的静止腺泡中急性激活c-Myc未能重新启动细胞周期或转变这些结构。c-Myc确实能在静止但结构无序的腺泡中重新启动细胞周期，这表明增殖阻滞需要适当的上皮结构。细胞极性蛋白PAR4的人类同源物LKB1的缺失也能恢复c-Myc在腺泡结构中重新启动细胞周期的能力。上皮结构也能抑制c-Myc的凋亡活性，但c-Myc与互补的肿瘤坏死因子相关凋亡诱导配体死亡受体途径的共同激活可在成熟腺泡中诱导强烈的Bim和Bid介导的凋亡反应。这些结果共同揭示了有组织的上皮结构令人惊讶的增殖和凋亡抗性，并确定了极性调节因子LKB1在耐c-Myc细胞组织发育中的作用。
