Lamina-associated polypeptide 2alpha regulates cell cycle progression and differentiation via the retinoblastoma-E2F pathway.
Lamina-associated polypeptide (LAP) 2alpha is a nonmembrane-bound LAP2 isoform that forms complexes with nucleoplasmic A-type lamins. In this study, we show that the overexpression of LAP2alpha in fibroblasts reduced proliferation and delayed entry into the cell cycle from a G0 arrest. In contrast, stable down-regulation of LAP2alpha by RNA interference accelerated proliferation and interfered with cell cycle exit upon serum starvation. The LAP2alpha-linked cell cycle phenotype is mediated by the retinoblastoma (Rb) protein because the LAP2alpha COOH terminus directly bound Rb, and overexpressed LAP2alpha inhibited E2F/Rb-dependent reporter gene activity in G1 phase in an Rb-dependent manner. Furthermore, LAP2alpha associated with promoter sequences in endogenous E2F/Rb-dependent target genes in vivo and negatively affected their expression. In addition, the expression of LAP2alpha in proliferating preadipocytes caused the accumulation of hypophosphorylated Rb, which is reminiscent of noncycling cells, and initiated partial differentiation into adipocytes. The effects of LAP2alpha on cell cycle progression and differentiation may be highly relevant for the cell- and tissue-specific phenotypes observed in laminopathic diseases.
Dorner
Daniela
D
Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, A-1030 Vienna, Austria.
Vlcek
Sylvia
S
Foeger
Nicole
N
Gajewski
Andreas
A
Makolm
Christian
C
Gotzmann
Josef
J
Hutchison
Christopher J
CJ
Foisner
Roland
R
D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D017930:Genes, Reporter / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D034881:Nuclear Lamina / Q000378:metabolism* / Q000648:ultrastructure; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000502:physiology; D034622:RNA Interference; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D016192:Resting Phase, Cell Cycle / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*
D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D008565:Membrane Proteins; D016160:Retinoblastoma Protein; C093413:lamina-associated polypeptide 2