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FRISC: The Faculty Research Interests Science Comparator |
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Assistant Professor, Center for Developmental Biology and Departments of Molecular
Biology and Internal Medicine
Genetics and
Development
Office: (214) 648-1481, (214) 648-1482, (214) 648-1612
FAX: (214) 648-1960
Building NB, Room 5.228
Email: graff02@utsw.swmed.edu
Center for Developmental Biology: http://www2.utsouthwestern.edu/devbio/
We are interested in the endogenous signals and signaling
pathways that control cell fate; that is, whether a cell will become a brain cell, a heart
cell, a blood cell, or a cancer cell. During development the signaling pathways are
normal, while during carcinogenesis the pathways are abnormal. We study both development
and cancer with the idea that the two systems will provide mutually synergistic
information. We have focused on the roles of TGFß and Wnt signaling as both pathways are
critical for normal development and components of both pathways are mutated in human
cancers. We primarily study these processes by exploiting the advantages provided by two
vertebrate model systems: the frog, Xenopus laevis , and the mouse.
A central task in developmental biology is the elucidation
of the mechanisms through which a radially symmetric egg becomes a patterned adult. In
vertebrates, pattern formation is mediated by growth factors that are secreted by one cell
and instruct other cells to adopt new fates. Little is known about the molecules that
direct the early steps of pattern information. TGFß and Wnt signaling molecules are
strong candidates for endogenous inducers and we have focused on isolating and
characterizing new components of these signal transduction cascades.
We have identified molecules that control formation of the
nervous system and the ventral (front) and the dorsal (back) sides of the body.
Furthermore, we identified a family of molecules, the Smads, that are the first known
members of the TGFß signaling cascade. The Smads are tumor suppressors and are mutated in
human cancers. We also recently identified a molecule that is a novel component of the Wnt
signaling pathway. Expression of this molecule generates embryos that have a duplicated
body plan, that is, Siamese twins.
To extend our studies from early development to models of
disease, we disrupt the developmentally important molecules through homologous
recombination in the mouse. One disease we study is colon cancer which affects 5% of
Americans and is the second leading cause of cancer related deaths. Of note, Wnt signaling
components and Smads are mutated in human colon cancers. To develop mouse models of colon
cancer, we generated Smad knockout mice. We found that 100% of Smad3 knockout mice develop
metastatic colon cancer that in many important ways mimics the human disease. We are using
this mouse model of colon cancer to understand the fundamental mechanisms of
carcinogenesis. In addition, we are undertaking genetic and pharmacological approaches to
develop preventative measures or cures for colon cancer.
Selected Publications:
Peters JM, McKay RM, McKay JP, and Graff
JM. (1999) Casein Kinase I transduces Wnt signals. Nature, 401, 345-350
LeSueur J, and Graff JM. (1999) Spemann organizer activity
of Smad10. Development 126, 137-146
Zhu Y, Richardson JA, Parada LF, and Graff JM. (1998)
Smad3 mutant mice develop metastatic colorectal cancer. Cell 94, 703-714
Graff JM. (1997) Embryonic Patterning: To BMP or not to
BMP, that is the question. Cell 89, 171-174
Graff JM, Bansal A, Melton DM. (1996) Xenopus Mad proteins
transduce distinct subsets of signals for the TGFß superfamily. Cell 85, 479-487
Graff JM, Thies RS, Song JJ, Celeste AJ, Melton DM. (1994)
Studies with a Xenopus BMP receptor suggest that ventral mesoderm-inducing signals
override dorsal signals in vivo. Cell 79, 169-179
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Last updated: 25 Sep 2001
Extraction Method: Expand using Medical Synonyms-
Eliminated words list: MedlinePlus List
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