Cortez D, Stoica G, Pierce J H, Pendergast A M
Department of Molecular Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Oncogene. 1996 Dec 19;13(12):2589-94.
BCR-ABL is a deregulated tyrosine kinase that is expressed in Philadelphia chromosome (Ph1) positive human leukemias. When expressed in hematopoietic cells, BCR-ABL causes cytokine independent proliferation, induces tumorigenic growth and prevents apoptosis in response to cytokine deprivation or DNA damage. One mechanism by which BCR-ABL signals in cells is by activating the small guanine nucleotide binding protein Ras. BCR-ABL-transformed cells have constitutively high levels of active, GTP-bound Ras. Here we use 32D cells that inducibly express a dominant negative Ras protein to define the Ras requirements in BCR-ABL-transformed cells. Dominant negative Ras inhibits BCR-ABL-mediated Ras activation, and induces cell death by an apoptotic mechanism. Therefore, BCR-ABL inhibits apoptosis through activation of a Ras-dependent signaling pathway.
BCR-ABL是一种失调的酪氨酸激酶，在费城染色体（Ph1）阳性的人类白血病中表达。当在造血细胞中表达时，BCR-ABL会导致细胞因子非依赖性增殖，诱导致瘤性生长，并在细胞因子剥夺或DNA损伤时阻止细胞凋亡。BCR-ABL在细胞中发出信号的一种机制是通过激活小GTP结合蛋白Ras。BCR-ABL转化的细胞具有持续高水平的活性、GTP结合的Ras。在这里，我们使用可诱导表达显性负性Ras蛋白的32D细胞来确定BCR-ABL转化细胞中对Ras的需求。显性负性Ras抑制BCR-ABL介导的Ras激活，并通过凋亡机制诱导细胞死亡。因此，BCR-ABL通过激活Ras依赖性信号通路来抑制细胞凋亡。
