While individual genes, regulatory factors, and events in the mammalian nucleus have been intensely studied and are beginning to be understood, the mechanisms by which the nucleus is organized and nuclear processes are coordinated remain largely unknown. Recently, the study of nuclear structure and function has taken on increased medical relevance with the discovery that A-type nuclear lamins, core constituents of the nuclear substructure, are targets for mutation in a wide variety of human diseases including dystrophic and progeroid syndromes (collectively termed laminopathies). An important question in understanding the molecular basis of the laminopathies is how mutations throughout the LMNA coding region could be associated with tissue-specific disorders. We have established a functional association between A-type lamins and the retinoblastoma protein (pRB), a known differentiation factor, regulator of cell proliferation and tumor suppressor. Lamin A/C protects pRB from proteosome-mediated degradation, pRB is required for normal differentiation of muscle and fat tissue, two of the tissues frequently affected in laminopathies. Moreover, pRB has been implicated in cellular senescence, a tissue culture model system for aging. A major focus of this proposal is to characterize the interactions between A-type lamins and pRB at a molecular and cellular level, and to determine whether lamin-dependent regulation of pRB is functionally significant in cell proliferation, stable tissue differentiation and the pathogenesis of laminopathies. We view the functional interaction between lamins and pRB as a prototype for how lamins coordinate nuclear regulatory proteins. Both directed and unbiased approaches will be initiated to identify novel, functionally significant lamin A/C interacting proteins. In vitro cell differentiation assays have served as important tools to identify key regulatory molecules that mediate cell specification. Given that A-type lamin expression is generally restricted to differentiating tissues and LMNA mutations cause dystrophic syndromes primarily affecting muscle and fat tissue, as a final Aim, a project has been initiated to examine the role of A-type lamins for myocyte and adipocyte differentiation. Myoblast cell lines, generated from Lmna-/- mice, exhibit differentiation defects. These defects will be studied at the molecular level to better understand how aberrant A-type lamin function leads to tissue degeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024287-04
Application #
7267625
Study Section
Special Emphasis Panel (ZRG1-CMAD (01))
Program Officer
Velazquez, Jose M
Project Start
2004-08-15
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
4
Fiscal Year
2007
Total Cost
$255,628
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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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
Schreiber, Katherine H; Kennedy, Brian K (2013) When lamins go bad: nuclear structure and disease. Cell 152:1365-75
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
Ramos, Fresnida J; Kaeberlein, Matt; Kennedy, Brian K (2013) Elevated MTORC1 signaling and impaired autophagy. Autophagy 9:108-9
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

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