School of Life Sciences, Singhania University, Pacheri Beri, Rajasthan, India.
Cell Biol Int. 2014 Jul;38(7):809-17. doi: 10.1002/cbin.10266. Epub 2014 Feb 27.
Tumour suppressor genes restrain inappropriate cell growth and division, as well as stimulate cell death to maintain tissue homeostasis. Loss of function leads to abnormal cellular behaviour, including hyperproliferation of cell and perturbation of cell cycle regulation. LIMD1 is a tumour suppressor gene located at chromosome 3p21.3, a region commonly deleted in many solid malignancies. LIMD1 interacts with retinoblastoma (Rb) and is involved in Rb-mediated downregulation of E2F1-target genes. However, the role of LIMD1 in cell cycle regulation remains unclear. We propose that LIMD1 induces cell cycle arrest, utilising Rb-E2F1 axis, and show that ectopic expression of LIMD1 in A549 cells results in hypo-phosphorylation that potentiates Rb function, which correlates with downregulation of E2F1. In agreement with these observations, LIMD1 overexpression retards cell cycle progression and blocks S-phase entry, as cells accumulate in G0/G1 phase and have reduced incorporation of BrdU. Most significantly, LIMD1-dependent effects on Rb function and cell cycle are reversed on depletion of endogenous LIMD1, underscoring its centrality in Rb-mediated cell cycle regulation. Hence, our findings provide new insight into cell cycle control by Rb-LIMD1 nexus.
肿瘤抑制基因抑制不适当的细胞生长和分裂，并刺激细胞死亡以维持组织内稳态。功能丧失会导致异常的细胞行为，包括细胞过度增殖和细胞周期调控失调。LIMD1 是位于染色体 3p21.3 上的肿瘤抑制基因，该区域在许多实体恶性肿瘤中经常缺失。LIMD1 与视网膜母细胞瘤（Rb）相互作用，并参与 Rb 介导的 E2F1 靶基因下调。然而，LIMD1 在细胞周期调控中的作用仍不清楚。我们提出 LIMD1 通过 Rb-E2F1 轴诱导细胞周期停滞，并表明在 A549 细胞中异位表达 LIMD1 导致 Rb 功能增强的低磷酸化，这与 E2F1 的下调相关。与这些观察结果一致，LIMD1 的过表达会减缓细胞周期进程并阻止 S 期进入，因为细胞在 G0/G1 期积累并且 BrdU 的掺入减少。最重要的是，内源性 LIMD1 耗尽会逆转 LIMD1 对 Rb 功能和细胞周期的影响，突出了其在 Rb 介导的细胞周期调控中的核心作用。因此，我们的发现为 Rb-LIMD1 连接体对细胞周期的控制提供了新的见解。
