A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation.
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.
Johnson
Brett R
BR
Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
Nitta
Ryan T
RT
Frock
Richard L
RL
Mounkes
Leslie
L
Barbie
David A
DA
Stewart
Colin L
CL
Harlow
Ed
E
Kennedy
Brian K
BK
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
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