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http://hdl.handle.net/11375/8128
Title: | A structural and functional analysis of cyclin interactions with the retinoblastoma protein family member P130 |
Authors: | Lacy, Susan E. |
Advisor: | M., Peter F. |
Department: | Medical Sciences |
Keywords: | Medical Sciences;Medical Sciences |
Publication Date: | Jun-1997 |
Abstract: | <p>pRb, p107 and p130 are structurally and functionally related polypeptides which comprise the retinoblastoma family of proteins. All three proteins are found in complexes with several cell cycle-regulating proteins, including cyclins and cyclin-dependent kinases (cdk's) which are thought to regulate the function of the pRb family members through phosphorylation. In vivo, p130 is observed in cyclin A/cdk2 and cyclin E/cdk2 complexes but not in complexes containing D-type cyclins and cdk4. This thesis examines these observations by identifying regions within the p130 sequence required for cyclin interactions. In vitro binding studies determined that D-type cyclin interactions require the majority of the "pocket domain" of p130. These interactions are disrupted upon phosphorylation of p130 by the cyclin D-associated kinase cdk4. Additional in vitro binding studies determined that a short sequence within the "spacer region" of p130 is required for interactions with cyclins A and E. This sequence contains an "RRL" motif which is present in several other cyclin A and cyclin E binding proteins. In vivo, the amino terminus of p130 is required to stabilize p130 interactions with cyclins A and E and this may be a result of inhibition of cdk2-associated kinase activity. Taken together, these results suggest that stable complexes containing p130 and cyclins A and E are not disrupted by phosphorylation of p130, perhaps because p130 inhibits the kinase activity of cdk2. In contrast, p130 interactions with D-type cyclins are disrupted in vivo because of cdk4-mediated phosphorylation of p130. This analysis concludes that D-type cyclin interactions with p130 are structurally and functionally distinct from interactions between p130 and cyclins A and E and these differences may be important in the regulation of p130 during the cell cycle.</p> |
URI: | http://hdl.handle.net/11375/8128 |
Identifier: | opendissertations/3359 4375 1591802 |
Appears in Collections: | Open Access Dissertations and Theses |
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fulltext.pdf | 7.64 MB | Adobe PDF | View/Open |
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