Regulation of the cyclin A1 protein is associated with its differential subcellular localization in hematopoietic and leukemic cells

Abstract

An important role of the cell cycle regulatory protein cyclin A1 in the development of acute myeloid leukemia (AML) was previously demonstrated in a transgenic mouse model. We have now turned our attention to study specific aspects of the activity and subcellular distribution of cyclin A1 using bone marrow samples from normal donors and patients with AML, as well as leukemic cell lines. We show that the localization of cyclin A1 in normal hematopoietic cells is nuclear, whereas in leukemic cells from AML patients and cell lines, it is predominantly cytoplasmic. In leukemic cell lines treated with all-trans retinoic acid (ATRA), cyclin A1 localized to the nucleus. Further, there was a direct interaction between cyclin A1 and cyclin-dependent kinase 1, as well as a major ATRA receptor, RARa, in ATRA-treated cells but not in untreated leukemic cells. Our results indicate that the altered intracellular distribution of cyclin A1 in leukemic cells correlates with the status of the leukemic phenotype.

Cyclin B1 and Other Cyclins as Tumor Antigens in Immunosurveillance and Immunotherapy of Cancer

“…AML patients whose tumors had high levels of cyclin A1 have significantly lower survival than those with low levels of cyclin A1 (19). In normal hematopoietic cells, cyclin A1 is predominantly nuclear; however, in leukemic cell lines and tumor cells from AML patients, cyclin A1 is predominantly cytoplasmic (20). Overexpression of cyclin A2, which is expressed in all dividing somatic cells, has also been associated with poor prognosis in several cancers (15).…”

A role for cyclin A1 in mediating the autocrine expression of vascular endothelial growth factor in prostate cancer

“…An important role for cyclin A1 in hematological malignancies has been demonstrated in a transgenic mouse model, in which targeted overexpression of cyclin A1 in early myeloid cells initiated acute myeloid leukemia (Liao et al, 2001). Further, the altered subcellular localization of cyclin A1 and the loss of its kinase partner, CDK1 in leukemic cells is linked to the leukemic phenotype (Ekberg et al, 2004). In male germ cells, cyclin A1 is absolutely required for the meiotic division as demonstrated by gene-targeting (Liu et al, 1998).…”

“…Coimmunoprecipitation and kinase assay were performed as described (Ekberg et al, 2004). In kinase assay, 50 mg/ml calf thymus histone H1 and GST-Rb (Upstate Biotech) were used as substrates.…”

Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia — The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms

“…The regulation of S-phase progression is summarized in Figure 2 and the altered regulation of this phase in human AML cells is described more in detail in Table 3 [49,98,99,102,[111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129]. The regulation of S-phase progression can be altered in primary AML cells, and the alterations can be both upstream and downstream to CDC25.…”