Seoane Marcos, Iglesias Pablo, Gonzalez Teresa, Dominguez Fernando, Fraga Maximo, Aliste Carlos, Forteza Jeronimo, Costoya Jose A
Molecular Oncology Lab, Departamento de Fisioloxia, Facultade de Medicina, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
PLoS One. 2008;3(11):e3632. doi: 10.1371/journal.pone.0003632. Epub 2008 Nov 5.
Senescence is one of the main barriers against tumor progression. Oncogenic signals in primary cells result in oncogene-induced senescence (OIS), crucial for protection against cancer development. It has been described in premalignant lesions that OIS requires DNA damage response (DDR) activation, safeguard of the integrity of the genome. Here we demonstrate how the cellular mechanisms involved in oncogenic transformation in a model of glioma uncouple OIS and DDR. We use this tumor type as a paradigm of oncogenic transformation. In human gliomas most of the genetic alterations that have been previously identified result in abnormal activation of cell growth signaling pathways and deregulation of cell cycle, features recapitulated in our model by oncogenic Ras expression and retinoblastoma (Rb) inactivation respectively. In this scenario, the absence of pRb confers a proliferative advantage and activates DDR to a greater extent in a DNA lesion-independent fashion than cells that express only HRas(V12). Moreover, Rb loss inactivates the stress kinase DDR-associated p38MAPK by specific Wip1-dependent dephosphorylation. Thus, Rb loss acts as a switch mediating the transition between premalignant lesions and cancer through DDR modulation. These findings may have important implications for the understanding the biology of gliomas and anticipate a new target, Wip1 phosphatase, for novel therapeutic strategies.
衰老 是肿瘤进展的主要障碍之一。原代细胞中的致癌信号会导致致癌基因诱导的衰老（OIS），这对于预防癌症发展至关重要。在癌前病变中已有描述，OIS 需要 DNA 损伤反应（DDR）激活，以保障基因组的完整性。在此，我们展示了在胶质瘤模型中，致癌转化所涉及的细胞机制是如何使 OIS 和 DDR 解偶联的。我们将这种肿瘤类型用作致癌转化的范例。在人类胶质瘤中，先前已鉴定出的大多数基因改变会导致细胞生长信号通路的异常激活和细胞周期失调，在我们的模型中，致癌性 Ras 表达和视网膜母细胞瘤（Rb）失活分别重现了这些特征。在这种情况下，但不表达 pRb 会赋予增殖优势，并以一种不依赖于 DNA 损伤的方式比仅表达 HRas(V12) 的细胞更强烈地激活 DDR。此外，Rb 缺失通过特定的 Wip1 依赖性去磷酸化作用使应激激酶 DDR 相关的 p38MAPK 失活。因此，Rb 缺失通过 DDR 调节作用充当了介导癌前病变与癌症之间转变的开关。这些发现可能对理解胶质瘤生物学具有重要意义，并为新的治疗策略预示了一个新靶点——Wip1 磷酸酶。
