Nuclear Lamin Functions and Human Disease

Buck Institute For Research On Aging, Novato CA

Investigators

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Abstract

DESCRIPTION (provided by applicant): Either through direct mutation or altered expression, A-type lamins have been linked to a number of diseases ranging from progeroid syndromes to tissue-specific dystrophies to cancer, indicating that this class of nuclear intermediate filament proteins plays a critical role in the maintenance of tissue homeostasis. A majority of the evidence indicates that LMNA mutations leading to progeria are dominant, acting as hypermorphs or neomorphs. In contrast, reduced lamin A/C expression is commonly associated with tumor progression. Findings from a number of studies indicate that lamin A is required for normal cell proliferation. Here we test the hypothesis that progeria results at least in part from impaired cell proliferation as a result of increased lamin A function, and that tumor progression instead results from loss of retinoblastoma family protein function and/or increased Gankyrin activity. To examine these related hypotheses, we have developed and will exploit a series of assays to better define the mechanisms underlying A-type lamin-dependent effects on cell proliferation. These include (1) an exploration of impaired proliferative phenotypes resulting from expression of progeria- associated mutants and studies to determine why increased telomerase activity restores normal proliferation, (2) further mechanistic studies to determine why A-type lamins act to stabilize the retinoblastoma protein, and (3) exploring the links between A-type lamins and Gankyrin expression. In a final approach, we will continue to examine similarities and differences between LMNA mutants linked to different diseases, using a non-biased approaches to identify lamin A interacting partners that specifically interact with wild-type lamin A or progerin. Considerable progress has been made to understand why LMNA mutations lead to progeria, particularly with regard to findings demonstrating that permanently farnesylated lamin A has a toxic effect on cells. Yet the mechanisms underlying that toxicity remain unknown. The strategies outlined in this proposal are designed to assess whether the toxicity caused by progerin and other progeria mutants are a result of altered cell proliferation. PUBLIC HEALTH RELEVANCE:: A-type lamins are targets for mutation in an increasing number of diseases that relate to altered cell proliferation, including progeroid syndromes that resemble premature aging. In this proposal, we describe experimental approaches to examine at the mechanistic level the role of A-type lamins in cell proliferation control. Findings from these studies will identify and test potential mechanistic underpinnings that underlie Hutchinson-Gilford progeria syndrome and other A-type lamin-associated diseases.