Rowlands Tracey M, Pechenkina Irina V, Hatsell Sarah J, Pestell Richard G, Cowin Pamela
Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11400-5. doi: 10.1073/pnas.1534601100. Epub 2003 Sep 17.
A considerable body of circumstantial data suggests that cyclin D1 is an attractive candidate to mediate the effects of beta-catenin in mammary tissue. To test the functional significance of these correlative findings, we investigated the genetic interaction between transcriptionally active beta-catenin (DeltaN89beta-catenin) and its target gene cyclin D1 in the mouse mammary gland during pubertal development, pregnancy, and tumorigenesis. Our data demonstrate that cyclin D1 is dispensable for the DeltaN89beta-catenin-stimulated initiation of alveologenesis in virgin females, for the de novo induction of alveoli in males, and for the formation of tumors. Indeed, lack of cyclin D1 accentuates and enhances these hyperplastic and tumorigenic DeltaN89beta-catenin phenotypes. Although alveologenesis is initiated by DeltaN89beta-catenin in a cyclin D1-independent fashion, up-regulation of cyclin D1 occurs in DeltaN89beta-catenin mice and its expression remains essential for the completion of alveolar development during the later stages of pregnancy. Thus, alveologenesis is a two-step process, and cyclin D1 activity during late alveologenesis cannot be replaced by the activity of other beta-catenin target genes that successfully drive proliferation at earlier stages.
大量的间接数据表明，细胞周期蛋白D1是介导β-连环蛋白在乳腺组织中作用的一个有吸引力的候选分子。为了测试这些相关发现的功能意义，我们研究了在青春期发育、怀孕和肿瘤发生过程中，转录活性β-连环蛋白（DeltaN89β-连环蛋白）与其靶基因细胞周期蛋白D1在小鼠乳腺中的遗传相互作用。我们的数据表明，细胞周期蛋白D1对于DeltaN89β-连环蛋白刺激处女雌性小鼠的肺泡形成起始、雄性小鼠肺泡的从头诱导以及肿瘤的形成是可有可无的。事实上，缺乏细胞周期蛋白D1会加剧并增强这些增生性和致瘤性的DeltaN89β-连环蛋白表型。虽然肺泡形成是由DeltaN89β-连环蛋白以不依赖细胞周期蛋白D1的方式起始的，但在DeltaN89β-连环蛋白小鼠中会出现细胞周期蛋白D1的上调，并且其表达对于怀孕后期肺泡发育的完成仍然至关重要。因此，肺泡形成是一个两步过程，并且在肺泡形成后期细胞周期蛋白D1的活性不能被其他在早期阶段成功驱动增殖的β-连环蛋白靶基因的活性所取代。
