Regulation of the wnt signaling pathway in Xenopus laevis.

Format:

Book

Thesis/Dissertation

Author/Creator:

Hedgepeth, Chester Melvin, III.

Contributor:

Klein, Peter S., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Biochemistry.

Molecular biology.

0307.

0487.

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

0307.

0487.

Physical Description:

184 pages

Contained In:

Dissertation Abstracts International 59-11B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

Wnt signaling has been implicated in both axis determination and patterning of mesodermal tissue in Xenopus as well as the onset of cancer. A combination of genetic and biochemical approaches in multiple organisms has yielded the intracellular mediators of the pathway. They include frizzled, dishevelled, glycogen synthase kinase-3 beta (GSK-3beta), beta-catenin, APC, and Tcf-LEF family members. GSK-3beta is a serine-threonine kinase and a negative regulator of the wnt signaling pathway. Our work has focused on the regulation of GSK-3beta activity by lithium and a newly identified gene, axin. Lithium perturbs the development of a number of organisms including Dictyostelium, sea urchin, and Xenopus and it has been shown that lithium directly inhibits GSK-3beta, providing an potential explanation for its developmental actions. Here, we extend this finding to show that lithium can potently inhibit GSK-3beta activity in vivo resulting in an accumulation of beta-catenin protein and activation of the wnt signaling pathway. To prove that GSK-3beta is the only target of lithium important in mediating its developmental effects, we have designed a screen in Saccharomyces cerevisiae to identify mutants of MDS-1, a GSK-3beta homologue, which are resistant to lithium treatment. In addition, in a yeast two hybrid screen using GSK-3beta as bait, we have identified Xenopus axin. Axin is a maternal gene which is also expressed strongly in the anterior midbrain. In vivo, axin binds GSK-3beta and mutants of axin lacking key regulatory domains act as dominant negatives by binding GSK-3beta and inhibiting its activity. These mutant forms of axin provide alternative, in vivo GSK-3betaB inhibitors which mimic the effect of lithium. We also provide evidence that an axin-GSK-3beta complex is important in the regulation of GSK-3beta activity. Our data suggests that axin may mediate inhibition as well as activation of wnt signaling through its interactions with GSK-3beta.

Notes:

Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 1998.

Source: Dissertation Abstracts International, Volume: 59-11, Section: B, page: 5709.

Adviser: Peter S. Klein.

Local Notes:

School code: 0175.

ISBN:

9780599120761

Access Restriction:

Restricted for use by site license.