The effects of crosstalk between Ras and cyclic AMP-dependent protein kinase A on thyrotropin-mediated signaling pathways.

Format:

Book

Thesis/Dissertation

Author/Creator:

Miller, Marsha Jean.

Contributor:

Meinkoth, Judy L., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Cytology.

Molecular biology.

0307.

0379.

Penn dissertations--Pathology.

Pathology--Penn dissertations.

Local Subjects:

Penn dissertations--Pathology.

Pathology--Penn dissertations.

0307.

0379.

Physical Description:

94 pages

Contained In:

Dissertation Abstracts International 59-07B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

The biological response to signal activation depends on the ability of cells to integrate concomitantly activated signaling pathways. At the molecular level, one of the best understood examples of such signaling crosstalk involves the interplay between Ras-mediated signaling and the second messenger cAMP. In some cells in which cAMP inhibits growth, cAMP prevents interaction of Ras with Raf, resulting in the inhibition of growth-factor stimulated MAPK activity. However, elevations in cAMP have been shown to stimulate proliferation in a number of cells, including Wistar rat thyroid (WRT) follicular cells. Thyrotropin (TSH), a regulator of WRT cells, elevates cAMP levels, which stimulates both cell proliferation and maintenance of the differentiated phenotype. Additionally, TSH-stimulated proliferation is dependent on Ras. The effects of overexpression of Ras effector domains, which signal through either Raf-dependent (RasV12S35) or Raf-independent (RasV12G37), were examined. In WRT cells expression of both RasV12G37 and RasV12S35 stimulates TSH-independent proliferation. However, TSH enhances proliferation in RasV12G37-expressing cells, while downregulating this process in RasV12S35 expressing cells. TSH also downregulates MAPK phosphorylation in RasV12S35-expressing cells, but stimulates MAPK phosphorylation in RasV12G37-expressing cells. RasV12S35 expression promotes dedifferentiation and transformation in WRT cells, whereas RasV12G37 expressing cells retain the parental phenotype. These results indicate that activation of different Ras effector pathways results in varied effects on the cells and that the channeling Ras signals to a particular effector pathway occurs in response to elevation of cAMP levels. RasV12G37 was used to identify RalGDS as a possible Ras effector utilized in response to TSH. Microinjection of thyroid cells with a RalGDS sequestering protein results in a reduction in TSH-stimulated DNA synthesis, suggesting a role for RalGDS in TSH-mediated signaling pathways in rat thyroid follicular cells.

Notes:

Thesis (Ph.D. in Pathology) -- University of Pennsylvania, 1998.

Source: Dissertation Abstracts International, Volume: 59-07, Section: B, page: 3182.

Adviser: Judy L. Meinkoth.

Local Notes:

School code: 0175.

ISBN:

9780591941012

Access Restriction:

Restricted for use by site license.