One of the major causes of genetic instability in cancer is errors in mitosis leading to unequal segregation of the genetic material between daughter cells. Many of the mitotic events and the checkpoints that monitor these events are yet to be understood at the molecular level. This is particularly true for the events that occur in late mitosis at the anaphase to telophase transition, when cells decondense their sister chromatids and reassemble their nuclei. In S. cerevisiae, the pathway that mediates these events is referred to as the mitotic exit network (MEN). In human cells a MEN pathway has not been characterized. However, a human protein kinase, Lats 1, has high sequence similarity to a yeast MEN kinase. Lats 1 has been implicated in mitosis, but its precise function is unclear. Nevertheless, Latsl is clearly linked to cancer development; in flies, mice and humans, Lats 1 is a well-established tumor suppressor protein. We hypothesize that Lats 1 functions in a MEN pathway in human cells and that deregulation of this pathway leads to genetic instability (as measured by loss-of-heterozygosity analysis). This hypothesis will be addressed by performing the following Specific Aims: 1. Establish that Lats 1 is the human ortholog of the S. cerevisiae Dbf2 MEN kinase. We will examine if Lats 1 shares with Dbf2 the ability to be regulated by Mob proteins. We will further examine whether Lats 1 functions in the MEN pathway in human cells using an siRNA approach and dominant negative mutants. 2. Establish that Lats 1 is regulated by hDmal. In S. pombe the MEN kinases are regulated by Dmal, a putative ubiquitin ligase. We will examine if human Lats 1 is regulated by hDmal, a ubiquitin ligase that has high sequence similarity with yeast Dmal. 3. Establish that deregulation of LATS 1 and hDmal increases the frequency of loss-of-heterozygosity (LOH). LOH is clearly involved in cancer development and progression. Thus, these studies will help identify the molecular basis for the tumor suppressor function of Lats 1.
| Tuttle, Robyn L; Bothos, John; Summers, Matthew K et al. (2007) Defective in mitotic arrest 1/ring finger 8 is a checkpoint protein that antagonizes the human mitotic exit network. Mol Cancer Res 5:1304-11 |
| Bothos, John; Tuttle, Robyn L; Ottey, Michelle et al. (2005) Human LATS1 is a mitotic exit network kinase. Cancer Res 65:6568-75 |
