Blocking p55PIK signaling inhibits proliferation and induces differentiation of leukemia cells.
p55PIK, a regulatory subunit of phosphatidylinositol 3-kinases, promotes cell cycle progression by interacting with cell cycle modulators such as retinoblastoma protein (Rb) via its unique amino-terminal 24 amino-acid residue (N24). Overexpression of N24 specifically inhibits these interactions and leads to cell cycle arrest. Herein, we describe the generation of a fusion protein (Tat transactivator protein (TAT)-N24) that contains the protein transduction domain and N24, and examined its effects on the proliferation and differentiation of leukemia cells. TAT-N24 not only blocks cell proliferation but remarkably induces differentiation of leukemia cells in vitro and in vivo. Systemically administered TAT-N24 also significantly decreases growth of leukemia cell tumors in animal models. Furthermore, overexpression of p55PIK in leukemia cells leads to increased proliferation; however, TAT-N24 blocks this effect and concomitantly induces differentiation. There is significant upregulation of p55PIK mRNA and protein expression in leukemia cells from patients. TAT-N24 inhibits cell cycle progression and induces differentiation of bone marrow cells derived from patients with several different types of leukemia. These results show that cell-permeable N24 peptide induces leukemia cell differentiation and suggest that p55PIK may be a novel drug target for the treatment of hematopoetic malignancies.
Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China.
G
G
Wang
Y
Y
Deng
X
X
Cao
S
S
Lai
Y
Y
Tong
X
X
Luo
Y
Y
Feng
X
X
Xia
J
J
Gong
J
J
Hu
D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D049109:Cell Proliferation; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D039481:CD11b Antigen; D015696:Gene Products, tat; D018950:Lipopolysaccharide Receptors; D011993:Recombinant Fusion Proteins; D019869:Phosphatidylinositol 3-Kinases; C523442:PIK3R3 protein, human