Blocking p55PIK signaling inhibits proliferation and induces differentiation of leukemia cells

Abstract

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 cellpermeable N24 peptide induces leukemia cell differentiation and suggest that p55PIK may be a novel drug target for the treatment of hematopoetic malignancies.

MicroRNA-432 targeting E2F3 and P55PIK inhibits myogenesis through PI3K/AKT/mTOR signaling pathway

“…class I PI3Ks are heterodimers with a regulatory subunit and a catalytic subunit. 24 P55PIK, playing an important role in PI3K/Akt-mediated biological processes, 25,26 could interact with cell cycle modulators such as retinoblastoma protein (Rb) 27 to promote cell cycle progression in leukemia cells 28 and other cancer cells. 29 During apoptosis, P55PIK undergoes cleavage by Caspase 6 (C6), and degenerated P55PIK will be dislocated in cells and cause cell cycle defects.…”

PIK3R3 Induces Epithelial-to-Mesenchymal Transition and Promotes Metastasis in Colorectal Cancer

“…Full-length human PIK3R3 was isolated as described previously (23) and cDNA subcloned into pCDNA3 plasmids. Sequence-verified constructs were used in all experiments.…”

RNAi-based functional selection identifies novel cell migration determinants dependent on PI3K and AKT pathways

“…Our data indicate that p55g was critically involved in the receptor tyrosine kinase Alk-promoted PI3K/AKT activation and cell migration. In the previous reports, p55g regulatory subunit of PI3K promoted cell cycle progression 56 , DNA synthesis 57 , proliferation and differentiation of leukemia cells 58 , and tumour angiogenesis via regulation of NF-kB signalling or expression of VEGF-A 59 . Furthermore, the protein levels of p55g increased in colorectal, gastric and ovarian cancers 56,59,60 .…”