Novel Insights into the Role of Kras in Myeloid Differentiation: Engaging with Wnt/beta-Catenin Signaling

卷:12

Review

关键词: COLONY-STIMULATING FACTOR;    GLYCOGEN-SYNTHASE KINASE-3;    BINDING PROTEIN ALPHA;    LEUKEMIA-CELL LINE;    TRANS-RETINOIC ACID;    BETA-CATENIN;    G-CSF;    FACTOR-RECEPTOR;    SELF-RENEWAL;    K-RAS;   

DOI  :  10.3390/cells12020322

来源: SCIE

【 摘 要 】

Cells of the HL-60 myeloid leukemia cell line can be differentiated into neutrophil-like cells by treatment with dimethyl sulfoxide (DMSO). The molecular mechanisms involved in this differentiation process, however, remain unclear. This review focuses on the differentiation of HL-60 cells. Although the Ras proteins, a group of small GTP-binding proteins, are ubiquitously expressed and highly homologous, each has specific molecular functions. Kras was shown to be essential for normal mouse development, whereas Hras and Nras are not. Kras knockout mice develop profound hematopoietic defects, indicating that Kras is required for hematopoiesis in adults. The Wnt/beta-catenin signaling pathway plays a crucial role in regulating the homeostasis of hematopoietic cells. The protein beta-catenin is a key player in the Wnt/beta-catenin signaling pathway. A great deal of evidence shows that the Wnt/beta-catenin signaling pathway is deregulated in malignant tumors, including hematological malignancies. Wild-type Kras acts as a tumor suppressor during DMSO-induced differentiation of HL-60 cells. Upon DMSO treatment, Kras translocates to the plasma membrane, and its activity is enhanced. Inhibition of Kras attenuates CD11b expression. DMSO also elevates levels of GSK3 beta phosphorylation, resulting in the release of unphosphorylated beta-catenin from the beta-catenin destruction complex and its accumulation in the cytoplasm. The accumulated beta-catenin subsequently translocates into the nucleus. Inhibition of Kras attenuates Lef/Tcf-sensitive transcription activity. Thus, upon treatment of HL-60 cells with DMSO, wild-type Kras reacts with the Wnt/beta-catenin pathway, thereby regulating the granulocytic differentiation of HL-60 cells. Wild-type Kras and the Wnt/beta-catenin signaling pathway are activated sequentially, increasing the levels of expression of C/EBP alpha, C/EBP epsilon, and granulocyte colony-stimulating factor (G-CSF) receptor.