A-type cyclins (cyclins A1 and A2) belong to the core cell cycle machinery. Cyclin A1 is expressed in the testes in the male germline, whereas cyclin A2 is ubiquitously expressed in all proliferating cells. Cyclin A2, together with its catalytic partners Cdk1 and Cdk2 is thought to drive S-phase progression by phosphorylating key proteins involved in DNA replication. In addition, cyclin A2 was postulated to play a role in entry of cells into mitosis, by regulating nuclear envelope breakdown and accumulation of cyclin B. It has been assumed that cyclin A represents an essential protein which is required for proliferation of all cell types. Consistent with this notion, cyclin A2-/- mice die shortly after implantation. Cyclin A2 is frequently overexpressed in different human cancer types. Moreover, this cyclin was postulated to represent a cell cycle recipient of c-Myc driven oncogenic pathways. Collectively, these observations suggest that cyclin A2 might represent an attractive therapeutic target in human neoplasia. However, the notion that cyclin A2 is essential for proliferation of all cell types has discouraged exploring this possibility. Duing the last funding period, we used conditional cyclin A knockout mice (cyclin A1-/-A2F/F) to bypass the embryonic lethality of cyclin A-null animals, and to test the requirement for cyclin A function at later stages of development. We found that cyclin A is dispensable for proliferation of several cell types. Our molecular analyses of fibroblasts revealed that A-type and E-type cyclins play redundant functions in cell cycle progression. We demonstrated that combined ablation of all A- and E-cyclins blocked proliferation of cyclin E1-/-E2-/-A1-/-A2?/? fibroblasts. In contrast, we observed that A-cyclins play an essential function in hematopoietic stem cells and in embryonic stem (ES) cells. Intriguingly, we observed that ES cells express relatively lower levels of cyclin E, which might explain their dependence on cyclin A. Alternatively, cyclin A may play a molecularly distinct role in stem cells, which cannot be carried out by E-cyclins. The molecular basis of the dependence of stem cells on cyclin A function remains unknown, and will be studied in this application in Aims 1 and 2. Lastly, in Aim 3 we will use conditional cyclin A knockout mice to test whether cyclin A is required for initiation and maintenance of c-Myc-driven breast cancers.
The specific Aims are as follows:
Specific Aim 1. To determine whether cyclin A plays a unique function in stem cells, and to elucidate the exact cellular mechanism in which cyclin A plays a rate-limiting role.
Specific Aim 2. To determine the molecular function of cyclin A-Cdk1 in stem cells.
Specific Aim 3. To test the requirement for cyclin A function in Myc-driven breast cancers.
This study focuses on a protein called cyclin A which is believed to play an important role in human cancers. We will study the molecular function of this protein in normal cells, and we will test whether turning off this protein in breast cancer cells would shut off cancer progression. This study may validate cyclin A as a novel and attractive therapeutic target in an aggressive subset of human breast cancers.
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