Cks (Cdc kinase subunit) proteins were originally identified through their ability to genetically suppress defective alleles of the cyclin-dependent kinases (CDKs) of both fission and budding yeast. Subsequent investigations demonstrated that these small (9-18kD) proteins were ubiquitous in eukaryotes and could directly bind to CDK/cyclin complexes, hence the designation Cks. Humans and other mammals express two Cks paralogs, which are often overexpressed in cancer, which in some cases is associated with aggressive disease and poor survival. Yet neither the precise essential function(s) of these proteins nor their role in oncogenesis has been elucidated. The current proposal aims to use molecular and molecular genetic approaches to determine the essential functions of Cks1 and Cks2 in mammalian cells. Furthermore, the cellular effects of Cks protein overexpression will be explored to elucidate the link to malignancy. Finally, mouse tumor models will be used to determine if partial loss of Cks protein function can be protective against malignancy, potentially validating functional interactions between Cks protein-protein as therapeutic targets.

Public Health Relevance

Cancer is a disease with tremendous health implications for the US and world. Yet, only limited progress has been made in curing most types of cancer. In part, this is because many mechanistic questions concerning the basic biology of cancer remain unanswered. This proposal seeks to address some of these unanswered questions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074224-14
Application #
8264774
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Hildesheim, Jeffrey
Project Start
1997-04-18
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
14
Fiscal Year
2012
Total Cost
$412,225
Indirect Cost
$195,150
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
del Rincón, S V; Widschwendter, M; Sun, D et al. (2015) Cks overexpression enhances chemotherapeutic efficacy by overriding DNA damage checkpoints. Oncogene 34:1961-7
Pan, Yen-Ru; Sun, Michael; Wohlschlegel, James et al. (2013) Cks1 enhances transcription efficiency at the GAL1 locus by linking the Paf1 complex to the 19S proteasome. Eukaryot Cell 12:1192-201
Teixeira, Leonardo K; Reed, Steven I (2013) Ubiquitin ligases and cell cycle control. Annu Rev Biochem 82:387-414
Liberal, Vasco; Martinsson-Ahlzen, Hanna-Stina; Liberal, Jennifer et al. (2012) Cyclin-dependent kinase subunit (Cks) 1 or Cks2 overexpression overrides the DNA damage response barrier triggered by activated oncoproteins. Proc Natl Acad Sci U S A 109:2754-9
Martinsson-Ahlzen, Hanna-Stina; Liberal, Vasco; Grunenfelder, Bjorn et al. (2008) Cyclin-dependent kinase-associated proteins Cks1 and Cks2 are essential during early embryogenesis and for cell cycle progression in somatic cells. Mol Cell Biol 28:5698-709
Xu, Kui; Belunis, Charles; Chu, Wei et al. (2003) Protein-protein interactions involved in the recognition of p27 by E3 ubiquitin ligase. Biochem J 371:957-64
Spruck, Charles H; de Miguel, Maria P; Smith, Adrian P L et al. (2003) Requirement of Cks2 for the first metaphase/anaphase transition of mammalian meiosis. Science 300:647-50
Spruck, Charles H; Strohmaier, Heimo M (2002) Seek and destroy: SCF ubiquitin ligases in mammalian cell cycle control. Cell Cycle 1:250-4
Spruck, C; Strohmaier, H; Watson, M et al. (2001) A CDK-independent function of mammalian Cks1: targeting of SCF(Skp2) to the CDK inhibitor p27Kip1. Mol Cell 7:639-50