Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Oncogene. 2013 Oct;32(40):4798-805. doi: 10.1038/onc.2012.496. Epub 2012 Nov 12.
The pocket proteins pRB, p107 and p130 have established roles in regulating the cell cycle through the control of E2F activity. The pocket proteins regulate differentiation of a number of tissues in both cell cycle-dependent and -independent manners. Prior studies showed that mutation of p107 and p130 in the mouse leads to defects in cartilage development during endochondral ossification, the process by which long bones form. Despite evidence of a role for pRB in osteoblast differentiation, it is unknown whether it functions during cartilage development. Here, we show that mutation of Rb in the early mesenchyme of p107-mutant mice results in severe cartilage defects in the growth plates of long bones. This is attributable to inappropriate chondrocyte proliferation that persists after birth and leads to the formation of enchondromas in the growth plates as early as 8 weeks of age. Genetic crosses show that development of these tumorigenic lesions is E2f3 dependent. These results reveal an overlapping role for pRB and p107 in cartilage development, endochondral ossification and enchondroma formation that reflects their coordination of cell-cycle exit at appropriate developmental stages.
口袋蛋白 pRB、p107 和 p130 通过控制 E2F 活性在细胞周期调控中发挥重要作用。口袋蛋白通过细胞周期依赖和非依赖的方式调节许多组织的分化。先前的研究表明，在小鼠中突变 p107 和 p130 会导致软骨发育过程中的软骨发育不良，即长骨形成的过程中出现缺陷。尽管有证据表明 pRB 在成骨细胞分化中发挥作用，但尚不清楚其在软骨发育过程中是否发挥作用。在这里，我们发现，在 p107 突变小鼠的早期间充质中突变 Rb 会导致长骨生长板中的严重软骨缺陷。这归因于出生后持续存在的不适当软骨细胞增殖，导致在 8 周龄时生长板中形成软骨瘤。遗传杂交表明，这些致瘤病变的发展依赖于 E2f3。这些结果揭示了 pRB 和 p107 在软骨发育、软骨内骨化和软骨瘤形成中的重叠作用，反映了它们在适当的发育阶段协调细胞周期退出的作用。
