Cyclin A Is Redundant in Fibroblasts but Essential in Hematopoietic and Embryonic Stem Cells

Abstract

SUMMARY Cyclin A, the first cyclin ever cloned, is thought to be an essential component of the cell cycle engine. Mammalian cells encode two A-type cyclins, testis-specific cyclin A1 and ubiquitously expressed cyclin A2. Here we tested the requirement for cyclin A function using conditional knockout mice lacking both A-type cyclins. We found that acute ablation of cyclin A in fibroblasts did not affect cell proliferation, but led to prolonged expression of cyclin E across the cell cycle. However, combined ablation of all A- and E-type cyclins extinguished cell division. Hence, in fibroblasts cyclins A and E play redundant roles in cell proliferation. In contrast, ablation of cyclin A in bone marrow obliterated hematopoiesis. We found that cyclin A function was essential for proliferation of hematopoietic and embryonal stem cells. In these compartments cyclin A-Cdk complexes are expressed at particularly high levels, which may render stem cells dependent on cyclin A.

Cyclin A1 Is Essential for Setting the Pluripotent State and Reducing Tumorigenicity of Induced Pluripotent Stem Cells

“…Taken together, these data suggest that modification of cyclin A 1 protein levels closer to that of mESCs (lower levels) can refine the pluripotent state of iPS cells. Interestingly, knockdown of cyclin A 1 in mESCs resulted in no chimeric mice born, with embryos dying at a very early stage of embryo development (data not shown), supporting previous work that cyclin A is essential for mESC survival, although that work did not distinguish between cyclin A 1 and A 2 [10]. We advance that work to show that cyclin A 1 is essential for mouse embryo development and survival.…”

“…We found a number of protein targets already known for having a critical role in ESC pluripotency such as ERK, SMAD4, and cyclin A, further validating this approach [10,11] (Fig. 1).…”

“…2). Because a recent in vivo study functionally demonstrated that cyclin A is specific for mESC survival [10], suggesting a role for the cell cycle kinase in maintaining pluripotency and that we had validated high levels of cyclin A 1 in partially reprogrammed hiPS, we focused on cyclin A 1 .…”

“…First, cyclin A 1 has been found to be essential for mESC survival, but not mouse fibroblasts, suggesting a role in pluripotency [10], and second, our unbiased antibody array screen identified cyclin A 1 as overexpressed in iPS cells compared to ESCs, the gold standard for ground state pluripotency, suggesting that during reprogramming, cyclin A 1 protein expression levels are not set correctly.…”

Inhibitor of Cyclin-dependent Kinase (CDK) Interacting with Cyclin A1 (INCA1) Regulates Proliferation and Is Repressed by Oncogenic Signaling

“…For example, mice could unexpectedly compensate their deficiency endogenously for RB (19), CDK2 (20,21), CDK4 (22), cyclin E (23,24), or for CDK inhibitors (25)(26)(27)(28)(29)(30). To our knowledge, the only cell cycle factor that leads to embryonic lethality, when deleted as singular factor, was cyclin A2 (31,32). These findings indicate that the many open questions have not been answered yet concerning cell cycle regulation.…”