Download Poster

Center for
BioMolecular
Modeling
…where teachers come first.
“Flipping on the Switch”: Ras & NF1
Wauwatosa West SMART Team: Shazia Ali, Jessica Hoffmann, Annie Davidson-Keup, Ben Schrank
Advisors: Mrs. Donnie Case, Mrs. Mary-Anne Haasch
Mentor: Dr. Robert Deschenes, Medical College of Wisconsin
Abstract
RAS is a signal transducer, a
molecular switch with two states: an
“on” state, which contains the GTP
nucleic acid, and an “off” state, which
contains the GDP nucleic acid. The
“switch” is turned on by growth factor
receptors such as epidermal growth
factor (EGF) and results in Ras
binding GTP. Once in the “on” state,
RAS interacts with another growth
activator, the Raf oncogene.
Activation of Raf initiates a cascade of
kinases that leads to an increase in
gene expression and stimulation of
cell growth.
In order to terminate the Ras
activation signal, GTP is hydrolyzed
to GDP resulting in Ras-GDP, the
“off” state of Ras. This is
accomplished with the help of a
GTPase activating protein, NF1. The
action of NF1 is to turn off Ras and
hence it is a tumor suppressor. NF1 is
also called Neurofibromin. The loss of
NF1 via genetic mutations causes a
cancer called neurofibromatosis.
Cancer
#1
•Uninhibited growth of cells due
to mutations
The Cell
EGF
•Activators initiate cell division
•Ex: RAS
-----------
#2
(RAS)
+
#3
+
RAF
A signal, such as
epidermal growth
factor (EGF), is sent to
a receptor on the cell.
This signal starts the
cell division process.
•Ex: NF1
•Cancer results from the
inappropriate expression of these
activators and/or inhibitors.
(NF1)
Switch On
(Cell Division)
#1
•Inhibitors, found in cells, stop
cell division
Switch Off
(No Cell Division)
#2
From there, the
oncogene RAS
interacts with another
growth activator, Raf.
Activation of Raf
initiates a cascade of
kinases that lead to
cell division
Our project explores how the Ras
protein interacts with NF1 to stimulate
the hydrolysis of GTP to turn off the
Ras oncogene protein. Scientists are
interested in this interaction because it• tumor growth and skin or bone irregularities
contributes to the understanding of • inherited by birth
cancer and potentially the design of
• 30-50% of new cases arise through mutations
drugs for Neurofibromatosis.
in NF1
Symptoms and Treatment
#3
OR
NF1 stops cell division by
hydrolyzing the GTP
portion of Ras into GDP.
This hydrolysis prevents
Ras from interacting with
Raf, and thus stops the
process.
Bibliography
Neurofibromatosis
• Cancer of the nervous system
• NF1 (a tumor suppressor) encodes
Neurofibromin, a protein that
inhibits the RAS oncogene’s
function.
• 1NF1, a neurofibromin, contains a
mutant structure that fails to
suppress the RAS oncogene
• This failure to suppress the RAS
oncogene causes unrestricted cell
proliferation, which can form
tumors if the cells are mutated
Barbacid, Mariano et all. “ Ras Oncogene: the first 30
years.” pages 7-13
Gutmann, David et all. “ Neurofibromatosis 1: Closing
the GAP between mice and men” pages 20-27
• symptoms include headache, facial pain and
numbness from pressure of tumors
Wittinghofer, Alfred et all. “ Structural analysis of the
GAP-related domain from neurofibromin and its
implications” pages 4313-4327
• treatment includes removal of tumors but no
effective cure has been found
Photos provided by: http://dentistry.ouhsc.edu and
www.theuniversityhospital.com
Supported by the National Institutes of Health (NIH) – National Center for Research Resources
Science Education Partnership Award (NCRR-SEPA)