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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024287-11
Application #
8505321
Study Section
Special Emphasis Panel (ZRG1-BDA-A (02))
Program Officer
Velazquez, Jose M
Project Start
2004-08-15
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
11
Fiscal Year
2013
Total Cost
$357,633
Indirect Cost
$173,286
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945
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Kennedy, Brian K; Pennypacker, Juniper K (2014) RB and lamins in cell cycle regulation and aging. Adv Exp Med Biol 773:127-42
Ramos, Fresnida J; Kaeberlein, Matt; Kennedy, Brian K (2013) Elevated MTORC1 signaling and impaired autophagy. Autophagy 9:108-9
Chen, Steven C; Kennedy, Brian K; Lampe, Paul D (2013) Phosphorylation of connexin43 on S279/282 may contribute to laminopathy-associated conduction defects. Exp Cell Res 319:888-96
Schreiber, Katherine H; Kennedy, Brian K (2013) When lamins go bad: nuclear structure and disease. Cell 152:1365-75
Ramos, Fresnida J; Chen, Steven C; Garelick, Michael G et al. (2012) Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci Transl Med 4:144ra103
Frock, Richard L; Chen, Steven C; Da, Dao-Fu et al. (2012) Cardiomyocyte-specific expression of lamin a improves cardiac function in Lmna-/- mice. PLoS One 7:e42918
Kruegel, Undine; Robison, Brett; Dange, Thomas et al. (2011) Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae. PLoS Genet 7:e1002253
Hale, J Scott; Frock, Richard L; Mamman, Sara A et al. (2010) Cell-extrinsic defective lymphocyte development in Lmna(-/-) mice. PLoS One 5:e10127
Lee, Damian C; Welton, K Linnea; Smith, Erica D et al. (2009) A-type nuclear lamins act as transcriptional repressors when targeted to promoters. Exp Cell Res 315:996-1007

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