p27Kip1 controls cell proliferation by binding to and regulating the activity of cyclin-dependent kinases (Cdks). Here we show that Cdk inhibition and p27 stability are regulated through direct phosphorylation by tyrosine kinases. A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL. Y88 phosphory...

AIMS Terminal differentiation of cardiac myocyte is associated with their permanent withdrawal from the cell cycle. In adult end-stage heart failure, significant numbers of myocytes express proliferating cell nuclear antigen yet fail to progress to cell division. Cyclin dependent kinase inhibitors are powerful inhibitors of the cell cycle and may play a direct role both in myocyte development a...

Acute myeloid leukemia (AML) is sustained by the extensive proliferation of leukemic stem and progenitor cells, which give rise to the population of leukemic blasts with defective differentiation and low proliferative capacity. We have recently shown that ligation of CD44, a cell surface molecule present on AML cells, with specific monoclonal antibodies (mAbs) inhibits their proliferation. Howe...

CD28 provides a costimulatory signal that cooperates with the TCR/CD3 complex to induce T cell activation, cytokine production, and clonal expansion. We have recently shown that CD28 directly regulates progression of T lymphocytes through the cell cycle. Although a number of signaling pathways have been linked to the TCR/CD3 and to CD28, it is not known how these two receptors cooperate to indu...

The role of p27(kip1) in Chronic Myeloid Leukemia (CML) has been well studied in relation to its function as a cell cycle inhibitor. However, its cytoplasmic function especially in CML remains to be seen. We studied the localization of p27(kip1) and its function during the progression of CML from chronic to blast phase. Our investigations revealed an increased localization of p27(kip1) in the c...

The tumor suppressor p27(Kip1) is an inhibitor of cyclin/cyclin-dependent kinase (CDK) complexes and plays a crucial role in cell cycle regulation. However, p27(Kip1) also has cell cycle-independent functions. Indeed, we find that p27(Kip1) regulates cell migration, as p27(Kip1)-null fibroblasts exhibit a dramatic decrease in motility compared with wild-type cells. The regulation of motility by...

p21Cip1 is a cyclin-dependent kinase (Cdk) inhibitor that is transcriptionally activated by p53 in response to DNA damage. We have explored the interaction of p21 with the currently known Cdks. p21 effectively inhibits Cdk2, Cdk3, Cdk4, and Cdk6 kinases (Ki 0.5-15 nM) but is much less effective toward Cdc2/cyclin B (Ki approximately 400 nM) and Cdk5/p35 (Ki > 2 microM), and does not associate w...

Infiltration of macrophages into tissue can promote tumour development. Depending on the extracellular matrix architecture, macrophages can adopt two migration modes: amoeboid migration--common to all leukocytes, and mesenchymal migration--restricted to macrophages and certain tumour cells. Here, we investigate the initiating mechanisms involved in macrophage mesenchymal migration. We show that...

Purpose: p27(p27) is a universal cyclin-dependent kinase inhibitor that inhibits cell cycle transition from G1 to S phase and is primarily regulated at the post-transcriptional level via the ubiquitin-proteasome pathway. In vitro data suggest that p27 degradation may be accelerated by the c-Jun activation domain binding protein-1 (JAB1), originally identified as a coactivator of the gene regula...

Growth factor erv1-like (Gfer) is an evolutionarily conserved sulfhydryl oxidase that is enriched in embryonic and adult stem cells and plays an essential prosurvival role in pluripotent embryonic stem cells. Here we show that knockdown (KD) of Gfer in hematopoietic stem cells (HSCs) compromises their in vivo engraftment potential and triggers a hyper-proliferative response that leads to their ...