The activation of proto-oncogenes and the inactivation of tumor suppressors drive tumor formation in vivo and the transformation of cells in culture. However, other genes that contribute to the transduction of oncogenic signals can modify tumor susceptibility. Kinase Suppressor of Ras 1 (KSR1) is a modifier of tumorigenesis and cell transformation by oncogenic Ras. The goal of this research is to explain the molecular mechanisms underlying the action of KSR1. Recent data from this laboratory demonstrate that KSR1 has properties expected of a molecular scaffold for the Raf/MEK/ERK signaling cassette. Furthermore, deletion of KSR1 prevents constitutively active RasV12 from transforming cells in culture and markedly diminishes RasV12-induced tumor formation in vivo. New data demonstrate that KSR1 interacts with caveolin-1 to regulate the subcellular assembly and activation of the Raf/MEK/ERK signaling cassette in a manner critical to RasV12-induced transformation and tumorigenesis. Experiments also demonstrate that the related protein, KSR2, has a distinct effect on cell proliferation and metabolism. A third set of studies reveal the interaction of KSR proteins with a kinase family that affects their function. These observations suggest a previously unidentified, but physiologically important, interdependence of mechanisms contributing to tumorigenesis via the Raf/MEK/ERK signaling cassette and mechanisms regulating cellular metabolism. This proposal will test the hypothesis that KSR proteins affect tumorigenic potential via mechanisms that are dependent and independent of the Raf/MEK/ERK kinase cascade. The details of those mechanisms will be revealed by: 1) determining the contribution of KSR1 in the spatial regulation of ERK activation and cell transformation, 2) determining the role of KSR2 in regulating KSR1 function and RasV12 tumorigenesis, and 3) determining the role of effectors of energy balance in regulating KSR proteins and activated RasV12.

Public Health Relevance

The proto-oncogene Ras is a commonly mutated contributor to multiple human cancers. KSR1 plays a potent role in regulating the tumorigenic potential of Ras. Thus, study of KSR proteins in the regulation of tumor formation is likely to provide novel insights into the molecular mechanisms regulating cancer susceptibility.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090400-10
Application #
8305038
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Watson, Joanna M
Project Start
2001-04-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$257,885
Indirect Cost
$84,225
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Guo, Lili; Volle, Deanna J; Lewis, Robert E (2014) Identification of a truncated kinase suppressor of Ras 2 mRNA in sperm. FEBS Open Bio 4:420-5
Potts, Malia B; Kim, Hyun Seok; Fisher, Kurt W et al. (2013) Using functional signature ontology (FUSION) to identify mechanisms of action for natural products. Sci Signal 6:ra90
Eritja, Nuria; Mirantes, Cristina; Llobet, David et al. (2012) ERýý-mediated repression of pro-inflammatory cytokine expression by glucocorticoids reveals a crucial role for TNFýý and IL1ýý in lumen formation and maintenance. J Cell Sci 125:1929-44
Klutho, Paula J; Costanzo-Garvey, Diane L; Lewis, Robert E (2011) Regulation of glucose homeostasis by KSR1 and MARK2. PLoS One 6:e29304
Fisher, Kurt W; Das, Binita; Kortum, Robert L et al. (2011) Kinase suppressor of ras 1 (KSR1) regulates PGC1? and estrogen-related receptor ? to promote oncogenic Ras-dependent anchorage-independent growth. Mol Cell Biol 31:2453-61
Llobet, David; Eritja, Nuria; Domingo, Monica et al. (2011) KSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levels. Am J Pathol 178:1529-43
Razidlo, Gina L; Johnson, Heidi J; Stoeger, Scott M et al. (2009) KSR1 is required for cell cycle reinitiation following DNA damage. J Biol Chem 284:6705-15
Kortum, Robert L; Johnson, Heidi J; Costanzo, Diane L et al. (2006) The molecular scaffold kinase suppressor of Ras 1 is a modifier of RasV12-induced and replicative senescence. Mol Cell Biol 26:2202-14
Kortum, Robert L; Costanzo, Diane L; Haferbier, Jamie et al. (2005) The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates adipogenesis. Mol Cell Biol 25:7592-604
Kortum, Robert L; Lewis, Robert E (2004) The molecular scaffold KSR1 regulates the proliferative and oncogenic potential of cells. Mol Cell Biol 24:4407-16

Showing the most recent 10 out of 12 publications