Genetic instability is one of the most important hallmarks of cancer. Associations of oncoproteins or tumor suppressors with the process of chromosome segregation provide possible links between carcinogenesis and chromosomal instability. Studies on the function of Rb have been centralized on its role in G1 phase but recently extended to G2/M phases of the cell cycle. Rb interacts with Heclp, through an IxCxE motif, specifically during G2/M phase. Inactivation of hsHeclp by microinjection with anti-Hecl monoclonal antibodies leads to cell death due to abnormal chromosomal segregation. Similarly, inactivation of scHEC1 in budding yeast results in lethality, which can be rescued by hsHEC 1, indicating a highly conserved function for this protein. Heclp appears to be a novel critical protein for M phase progression, and RB can increase the fidelity of chromosome segregation mediated by hsHec lp. Intriguingly, the expression of HEC 1 is highly elevated in most cancer cell lines. Based on these preliminary results, we plan to address the role of Heclp during chromosome segregation in mammalian cells and to explore the possibility of using the Heclp network as a target for developing small molecules that inactivate its function as potential therapeutic candidates. In this application, we proposed four specific aims to address these issues:
Aim 1 : To elucidate the biological significance of the interaction between Hec 1 and Hint 1 at kinetochores and to analyze the role of Heclp and Hintl in spindle checkpoint response.
Aim 2 : To elucidate the biological function of 15A2 and its interaction with Hecl at centrosomes and to analyze the role of Heclp and 15A2 in centrosome functions.
Aim 3 : To examine the regulatory phosphorylation of Hecl by identifying the responsible kinases and to determine roles of the phosphorylated Heclp during chromosome segregation;
and Aim 4 : To explore the Hec 1 networks for potentials as molecular therapeutic targets by identifying small molecules that disrupt the interactions between Heclp and Nek2 as therapeutic candidates. It is expected that elucidation of the function of Heclp will provide useful information in understanding the regulation of chromosome segregation. Moreover, the identified small molecules will not only be a useful tool for dissecting the mitotic machinery, but will have potentials for therapeutic application to treat cancer. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107568-21
Application #
7175302
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Spalholz, Barbara A
Project Start
1991-07-01
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
21
Fiscal Year
2007
Total Cost
$429,266
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Zhu, Jiewen; Chen, Hongyuan; Guo, Xuning Emily et al. (2015) Synthesis, molecular modeling, and biological evaluation of novel RAD51 inhibitors. Eur J Med Chem 96:196-208
Hu, C-M; Zhu, J; Guo, X E et al. (2015) Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism. Oncogene 34:1220-30
Guo, Xuning Emily; Ngo, Bryan; Modrek, Aram Sandaldjian et al. (2014) Targeting tumor suppressor networks for cancer therapeutics. Curr Drug Targets 15:2-16
Ngo, Bryan; Hu, Chun-Mei; Guo, Xuning Emily et al. (2013) Complementary interhelical interactions between three buried Glu-Lys pairs within three heptad repeats are essential for Hec1-Nuf2 heterodimerization and mitotic progression. J Biol Chem 288:34403-13
Wei, Randy; Ngo, Bryan; Wu, Guikai et al. (2011) Phosphorylation of the Ndc80 complex protein, HEC1, by Nek2 kinase modulates chromosome alignment and signaling of the spindle assembly checkpoint. Mol Biol Cell 22:3584-94
Tsai, Connie Y; Ngo, Bryan; Tapadia, Anjali et al. (2011) Aurora-A phosphorylates Augmin complex component Hice1 protein at an N-terminal serine/threonine cluster to modulate its microtubule binding activity during spindle assembly. J Biol Chem 286:30097-106
Lin, Li-Fang; Chuang, Chih-Hung; Li, Chien-Feng et al. (2010) ZBRK1 acts as a metastatic suppressor by directly regulating MMP9 in cervical cancer. Cancer Res 70:192-201
Wu, Guikai; Wei, Randy; Cheng, Eric et al. (2009) Hec1 contributes to mitotic centrosomal microtubule growth for proper spindle assembly through interaction with Hice1. Mol Biol Cell 20:4686-95
Qiu, Xiao-Long; Li, Guideng; Wu, Guikai et al. (2009) Synthesis and biological evaluation of a series of novel inhibitor of Nek2/Hec1 analogues. J Med Chem 52:1757-67
Wu, Guikai; Qiu, Xiao-Long; Zhou, Longen et al. (2008) Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal. Cancer Res 68:8393-9

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