Increased expression of cyclin A1 protein is associated with all-trans retinoic acid-induced apoptosis.

Deregulated cell growth and inhibition of apoptosis are hallmarks of cancer. All-trans retinoic acid induces clinical remission in patients with acute promyelocytic leukemia by inhibiting cell growth and inducing differentiation and apoptosis of the leukemic blasts. An important role of the cell cycle regulatory protein, cyclin A1, in the development of acute myeloid leukemia has previously been demonstrated in a transgenic mouse model. We have recently shown that there was a direct interaction between cyclin A1 and a major all-trans retinoic acid receptor, RAR alpha, following all-trans retinoic acid treatment of leukemic cells. In the present study, we investigated whether cyclin A1 might be involved in all-trans retinoic acid-induced apoptosis in U-937 leukemic cells. We found that all-trans retinoic acid-induced apoptosis was associated with concomitant increase in cyclin A1 expression. However, there was no induction of cyclin A1 mRNA expression following the all-trans retinoic acid-induced apoptosis. Treatment of cells with a caspase inhibitor was not able to prevent all-trans retinoic acid-induced up-regulation of cyclin A1 expression. Interestingly, induced cyclin A1 expression in U-937 cells led to a significant increase in the proportion of apoptotic cells. Further, U-937 cells overexpressing cyclin A1 appeared to be more sensitive to all-trans retinoic acid-induced apoptosis indicating the ability of cyclin A1 to mediate all-trans retinoic acid-induced apoptosis. Induced cyclin E expression was not able to initiate cell death in U-937 cells. Our results indicate that cyclin A1 might have a role in apoptosis by mediating all-trans retinoic acid-induced apoptosis.

Cyclin A1 expression and associations with disease characteristics in childhood acute lymphoblastic leukemia.

A critical cell cycle regulatory protein, cyclin A1, has been implicated in the development of acute myeloid leukemia (AML). Here, we have examined the expression and clinical significance of cyclin A1 in childhood acute lymphoblastic leukemia (ALL). Cyclin A1 was highly expressed in lymphoblastic leukemic cell lines and in 22 of 30 ALL patients (73%). Cyclin A1 expression correlated with patient age (P=0.006), but not with cytogenetic abnormalities. Patients with high levels of cyclin A1 had poorer event-free survival (57.9%) compared to patients with lower levels (75%).

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

Elevated levels of cyclin A1 expression have been implicated in acute myeloid leukemia and in male germ cell tumors. However, a role of cyclin A1 in tumorigenesis of prostate cancer has not been reported. In the present study, expression of cyclin A1 in patients with prostate cancer and a role of cyclin A1 in mediating expression of vascular endothelial growth factor (VEGF) were investigated. Cyclin A1 was highly expressed in aggressive tumors and was significantly correlated with VEGF expression in 96 patients with prostate cancer. Treatment of LNCaP cells with R1881, a synthetic androgen resulted in increased cyclin A1 expression. Induction of cyclin A1 expression in LNCaP cells led to an increase in VEGF expression and this effect was manifested upon the R1881 treatment. Cyclin A1 failed to mediate VEGF activation in DU-145 cells lacking a functional Rb and an androgen receptor (AR). Although AR expression was induced into DU-145 cells, cyclin A1 was unable to mediate VEGF expression. However, induced coexpression of cyclin A1, Rb and AR in DU-145 cells in the presence of R1881 greatly promoted VEGF promoter activity. This suggests that cyclin A1 mediates VEGF expression in cooperation with Rb- and androgen-dependent pathways in prostate cancer.

Molecular phylogeny of the speciose vole genus Microtus (Arvicolinae, Rodentia) inferred from mitochondrial DNA sequences.

Voles of the genus Microtus represent one of the most speciose mammalian genera in the Holarctic. We established a molecular phylogeny for Microtus to resolve contentious issues of systematic relationships and evolutionary history in this genus. A total of 81 specimens representing ten Microtus species endemic to Europe as well as eight Eurasian, six Asian and one Holarctic species were sequenced for the entire cytochrome b gene (1140 bp). A further 25 sequences were retrieved from GenBank, providing data on an additional 23, mainly Nearctic, Microtus species. Phylogenetic analysis of these 48 species generated four well-supported monophyletic lineages. The genus Chionomys, snow voles, formed a distinct and well-supported lineage separate from the genus Microtus. The subgenus Microtus formed the strongest supported lineage with two sublineages displaying a close relationship between the arvalis species group (common voles) and the socialis species group (social voles). Monophyly of the Palearctic pitymyid voles, subgenus Terricola, was supported, and this subgenus was also subdivided into two monophyletic species groups. Together, these groupings clarify long-standing taxonomic uncertainties in Microtus. In addition, the "Asian" and the Nearctic lineages reported previously were identified although the latter group was not supported. However, relationships among the main Microtus branches were not resolved, suggesting a rapid and potentially simultaneous radiation of a widespread ancestor early in the history of the genus. This and subsequent radiations discernible in the cytochrome b phylogeny, show the considerable potential of Microtus for analysis of historical and ecological determinants of speciation in small mammals. It is evident that speciation is an ongoing process in the genus and that the molecular data provides a vital insight into current species limits as well as cladogenic events of the past.