ABL致癌基因通过细胞周期蛋白D1进行信号传导。

Signaling by ABL oncogenes through cyclin D1.

作者信息

Afar D E, McLaughlin J, Sherr C J, Witte O N, Roussel M F

机构信息

Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90095, USA.

出版信息

Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9540-4. doi: 10.1073/pnas.92.21.9540.

Oncogenic signals induce cellular proliferation by deregulating the cell division cycle. Cyclin D1, a regulator of G1-phase progression, acts synergistically with ABL oncogenes in transforming fibroblasts and hematopoietic cells in culture. Synergy with v-Abl depended on a motif in cyclin D1 that mediates its binding to the retinoblastoma protein, suggesting that ABL oncogenes in part mediate their mitogenic effects via a retinoblastoma protein-dependent pathway. Overexpression of cyclin D1, but not cyclin E, rescued a signaling-defective src-homology 2 (SH2) domain mutant of BCR-ABL for transformation of cells in culture and malignant tumor formation in vivo. These results demonstrate that cyclin D1 can provide essential signals for malignant transformation in concert with an activated tyrosine kinase.

致癌信号通过解除对细胞分裂周期的调控来诱导细胞增殖。细胞周期蛋白D1是G1期进程的调节因子，在体外培养中，它与ABL致癌基因协同作用，促使成纤维细胞和造血细胞发生转化。与v-Abl的协同作用依赖于细胞周期蛋白D1中的一个基序，该基序介导其与视网膜母细胞瘤蛋白的结合，这表明ABL致癌基因部分地通过视网膜母细胞瘤蛋白依赖的途径介导其促有丝分裂作用。细胞周期蛋白D1而非细胞周期蛋白E的过表达挽救了BCR-ABL的信号缺陷型src同源2（SH2）结构域突变体，使其能够在体外培养中转化细胞并在体内形成恶性肿瘤。这些结果表明，细胞周期蛋白D1可以与活化的酪氨酸激酶协同为恶性转化提供必要信号。