INVESTIGATION OF LAMIN A PROCESSING AND REGULATION

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dc.contributor.advisorCao, Kanen_US
dc.contributor.authorWu, Dien_US
dc.contributor.departmentCell Biology & Molecular Geneticsen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2017-09-14T05:45:48Z
dc.date.available2017-09-14T05:45:48Z
dc.date.issued2017en_US
dc.description.abstractLamin A is a major component of the lamina, which creates a dynamic network underneath the nuclear envelope. Mutations in the lamin A gene (LMNA) cause severe genetic disorders. One of the most striking cases is Hutchinson-Gilford progeria syndrome (HGPS). It is caused by a lamin A mutant protein named progerin. Due to the abnormal retaining of a permanent C-terminal farnesyl tail, progerin gradually accumulates on the nuclear membrane, resulting in abnormal nuclear morphology during interphase and perturbing a diversity of signaling and transcriptional events. To better understand lamin A gene’s function and regulation, I studied lamin A from three aspects in my dissertation, including its post-translational processing, post-transcriptional degradation, and transcriptional regulation. For post-translational processing, I examined the potential effects of cytoplasmic progerin based on a previous observation that membrane-associated progerin forms visible cytoplasmic aggregates in mitosis. After removal of the nuclear localization signal, I find that both LAΔNLS and PGΔNLS mutants are farnesylated in the cytosol and associated with a sub-domain of the ER via their farnesyl tails. While the farnesylation on LAΔNLS can be gradually removed by Zempste24, PGΔNLS remains permanently farnesylated and aggregated in the cytosol. Moreover, both ΔNLS mutants dominantly affect emerin’s nuclear localization. Previously, the accumulation of progerin has led to the speculation that progerin is more stable than the wild type lamin A. However, the low solubility of lamin proteins renders traditional immunoprecipitation-dependent methods ineffective for comparing the relative stabilities of mutant and wild type lamins. Therefore, to investigate the post-translational degradation of lamin A, I employed a novel platform based on viral 2A peptide-mediated co-translational cleavage to infer differences in lamin stability. My results support the notion that progerin is more stable than lamin A. In addition, treatment of FTI reduces progerin relative stability to the level of wild type lamin A. Last but not the least, I investigated the function of LMNA first intron in order to better understand the transcription regulation of lamin A. My results show that a highly conserved region within LMNA first intron is essential for the expression repression of lamin A in HL60 cells. This process is fulfilled by the interaction between this conserved region and transcription factor Sp1. Taken together, my results reveal new insights into biogenesis, protein interaction and transcription regulation of lamin A.en_US
dc.identifierhttps://doi.org/10.13016/M2WM13T9N
dc.identifier.urihttp://hdl.handle.net/1903/19994
dc.language.isoenen_US
dc.subject.pqcontrolledCellular biologyen_US
dc.subject.pquncontrolledfirst intronen_US
dc.subject.pquncontrolledlamin Aen_US
dc.subject.pquncontrolledprocessingen_US
dc.subject.pquncontrolledprogerinen_US
dc.subject.pquncontrolledstabilityen_US
dc.subject.pquncontrolledtranscription regulationen_US
dc.titleINVESTIGATION OF LAMIN A PROCESSING AND REGULATIONen_US
dc.typeDissertationen_US

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