Human cell division is a highly coordinated set of events that ensures the proper transmission of genetic material (chromosomes) from one mother cell to two newly formed cells. Chromosome missegregation during cell division can lead to aneuploidy (an aberrant chromosomal number), which is a hallmark of most cancers and has been proposed to promote tumorigenesis. Critical to ensuring proper sister chromatid separation at the metaphase to anaphase transition is the multi-component spindle assembly checkpoint (SAC), which is activated when unattached kinetochores or nonproductive (monotelic, syntelic, and merotelic) attachments are sensed and functions to arrest cells in metaphase to give time to correct these deficiencies and generate proper microtubule-kinetochore attachments before proceeding with cell division. Interestingly, a functional SAC plays a role in the effectiveness of chemotherapeutic drugs like antimitotics (drugs that inhibit mitosis), which damage the mitotic spindle, activate the SAC, arrest cells in prometaphase and trigger apoptotic cell death. Because understanding the SAC is critical to understanding tumorigenesis and the response of tumor cells to antimitotic drugs, it has become an attractive area of research. Although the last 40 years of research has shed light on the SAC, we are far from elucidating the full complement of regulatory factors involved in this complex pathway and from understanding how misregulation of this pathway can lead to tumorigenesis and resistance to chemotherapeutic drugs like antimitotics. To address these issues, we recently performed a high-throughput small interfering RNA (siRNA) screen for novel regulators of the SAC. This approach yielded two novel cyclin dependent kinases (Cdk14 and Cdk15) and two dual specificity phosphatases (DUSP7 and DUSP12). Inactivation of these novel factors leads to SAC bypass in the presence of antimitotic drugs like Taxol, which normally activate the SAC and induce cell death. To our knowledge, these factors have not been previously linked to SAC functioning and have limited genetic and molecular characterization in general. Thus understanding how these factors regulate the SAC is important to understanding the SAC and more broadly cell division. We hypothesize that these factors are controlling the SAC through their phosphorylation and dephosphorylation activities. Thus, we will test this hypothesis by analyzing the function of these proteins during unperturbed cell divisions and in the presence of antimitotics that generate spindle damage and activate the spindle assembly checkpoint. We expect that our studies will identify and characterize new factors and pathways that regulate the SAC, that we will be able to map their roles in time and space, and that our contributions to understanding the mechanisms of cell division will impact future cancer studies and cancer patient quality of life and survival.

Public Health Relevance

Our research group has discovered several new proteins that regulate the spindle assembly checkpoint, which ensures the proper transmission of genetic material in dividing cells. We aim to understand how these proteins function to ensure that cells divide normally and to understand how their misregulation can lead to tumor formation and a reduced response to anticancer drugs. These studies will impact future studies aimed at improving cancer patient quality of life and survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM117475-02
Application #
9210112
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Deatherage, James F
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2017
Total Cost
$311,850
Indirect Cost
$109,350
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095