Dissertation/Thesis Abstract

A-Type Lamins in Cell Cycle Regulation
by Parman-Ryans, Jaime Lyn, Ph.D., East Tennessee State University, 2017, 91; 13830138
Abstract (Summary)

Proteins of the nuclear lamina provide structural support to the nuclear envelope and participate in a variety of cellular functions, such as chromatin organization and transcriptional regulation. One of these proteins, Lamin A (72kDa), is synthesized as a 74 kDa precursor protein, Prelamin A, which undergoes an unusual maturation pathway that requires two farnesylation-dependent endoproteolytic cleavages. The second cleavage is unique to lamin A in higher vertebrates and is specifically carried out by the endoprotease zmpste24. Although most previous studies have focused mainly on the function of mature Lamin A, recent evidence from our laboratory shows important biological functions for Prelamin A as well. Prelamin A concentration in proliferating cells is very low or undetectable. Conversely, during quiescence induced by mitogen withdrawal or contact inhibition, Prelamin A levels increase dramatically. These variations are directly regulated by changes in expression and enzymatic activity of zmpste24. The central hypothesis of this dissertation is that full-length farnesylated and carboxymethylated prelamin A (FC-PreA) antagonizes both proliferation and apoptosis, therefore playing a role in cellular quiescence/senescence. To accomplish this goal, we studied the transcriptional regulation of zmpste24 and the interaction of FC-preA with proteins that participate in cell cycle control. 1) We identified and characterized a functional site for the E2F1 transcription factor (involved in the control of cell cycle) in the proximal 5’ UTR region of zmpste24. 2) By using proximity-labeling and co-immunoprecipitation-mass spectrometry techniques, we identified a set of proteins that interact preferentially with L467R-Prelamin A (uncleavable mutant) but not with mature Lamin A. Many of these proteins function to regulate progression through cell cycle.

Indexing (document details)
Advisor: Rusinol, Antonio E.
Commitee: Defoe, Dennis, Hoover, Donald, Johnson, David, Rusinol, Antonio, Thewke, Doug
School: East Tennessee State University
Department: Biomedical Sciences
School Location: United States -- Tennessee
Source: DAI-B 80/06(E), Dissertation Abstracts International
Subjects: Cellular biology
Keywords: Cell cycle, Lamins
Publication Number: 13830138
ISBN: 978-0-438-79070-4
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