title: A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation.
abstract: The retinoblastoma protein (pRB) is a critical regulator of cell proliferation and differentiation and an important tumor suppressor. In the G(1) phase of the cell cycle, pRB localizes to perinucleolar sites associated with lamin A/C intranuclear foci. Here, we examine pRB function in cells lacking lamin A/C, finding that pRB levels are dramatically decreased and that the remaining pRB is mislocalized. We demonstrate that A-type lamins protect pRB from proteasomal degradation. Both pRB levels and localization are restored upon reintroduction of lamin A. Lmna(-/-) cells resemble Rb(-/-) cells, exhibiting altered cell-cycle properties and reduced capacity to undergo cell-cycle arrest in response to DNA damage. These findings establish a functional link between a core nuclear structural component and an important cell-cycle regulator. They further raise the possibility that altered pRB function may be a contributing factor in dystrophic syndromes arising from LMNA mutation.
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
authors.forename: Brett R
authors.initials: BR
authors.lastname: Johnson
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Nitta
authors.forename: Richard L
authors.initials: RL
authors.lastname: Frock
authors.forename: Leslie
authors.initials: L
authors.lastname: Mounkes
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Ed
authors.initials: E
authors.lastname: Harlow
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
mesh_terms: D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D000818:Animals; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005347:Fibroblasts; D017353:Gene Deletion; D034904:Lamin Type A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107
chemical_list: D034904:Lamin Type A; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; C489485:Rbl1 protein, mouse; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; C440308:lamin C; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex