Hematopoiesis is the formation of specific cell lineages in the blood through proliferation and differenatiation of pluripotent hematopoietic cells. The proto-oncogene c-myb encodes a transcription factor expressed predominantly in hematopoietic cells and plays a critical role in their proliferation, survival, and differentiation. Our preliminary data has identified neuromedin U (NmU) as a novel Myb gene target in K562 cells that were engineered to express a tamoxifen inducible dominant negative Myb (MERT). We also demonstrate that both c-myb and NmU are elevated in cell lysates from acute myeloid leukemia (AML) patients compared to normal donors. Cell lysates from AML patients and normal donors also express NmU receptor type-1 (NMUR1), a G-protein coupled receptor. In addition, exposing our K562 cell lines to NmU promoted cell proliferation and induced intracellular Ca+2 flux. Based on these observations, we hypothesize that NmU plays a key physiological role in hematopoietic cells. To test this hypothesis, I will study the regulation and function of NmU in hematopoietic cells with the following specific aims:
Aim #1 - Investigate NmU-mediated signal transduction in hematopoietic cells. To begin to unravel the mechanism of NmU action in hematopoietic cells, I will examine the ability of NmU to activate phospholipase C and protien kinase C.
Aim #2 - Examine the transcriptional regulation of NmU in hematopoietic cells.
This aim proposes studies to evaluate the role of Myb and c-fos in modulating NmU gene expression, because these motifs have been identified in the putative NmU promoter.
Aim #3 - Determine the importance of NmU during hematopoiesis.
This aim will focus on the ability of NmU to promote proliferation of hematopoietic cells through an autocrine loop and determine the effect NmU has on differentiating hematopoietic cells along the erythroid and megakaryocyte lineages. The proposed didactic training and research plan will facilitate the transition of this candidate into a productive independent investigator in the areas of hematopoiesis and stem cell biology.
| Gambone, Julia E; Dusaban, Stephanie S; Loperena, Roxana et al. (2011) The c-Myb target gene neuromedin U functions as a novel cofactor during the early stages of erythropoiesis. Blood 117:5733-43 |
| Nakata, Yuji; Shetzline, Susan; Sakashita, Chizuko et al. (2007) c-Myb contributes to G2/M cell cycle transition in human hematopoietic cells by direct regulation of cyclin B1 expression. Mol Cell Biol 27:2048-58 |
