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A more recent version of this article appeared on December 1, 2002
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Submitted on February 27, 2002
Revised on July 31, 2002
Accepted on August 29, 2002
is required for the nuclear anchorage of the retinoblastoma protein
1 The Department of Biological Sciences, The University of Durham, South Road, Durham DH1 3LE, UK
2 Institute of Biochemistry and Molecular Cell Biology, Vienna Biocenter, University of Vienna, A-1030 Vienna, Austria
* Corresponding author. E-mail address: c.j.hutchison{at}durham.ac.uk.
The phosphorylation-dependent anchorage of retinoblastoma protein Rb in the nucleus is essential for its function. We show that its pocket C domain is both necessary and sufficient for nuclear anchorage by transiently expressing GFP-chimeras of Rb fragments in tissue culture cells and extracting the cells with hypotonic solutions. Solid phase binding assays using GST-fusion of Rb pockets A, B and C revealed a direct association of lamin C exclusively to pocket C. Lamina-associated polypeptide (LAP) 2
, a binding partner of lamins A/C, bound strongly to pocket C and weakly to pocket B. When LAP2 was immunoprecipitated from soluble nuclear fractions, lamins A/C and hypophosphorylated Rb were co-precipitated efficiently. Similarly, immunoprecipitation of expressed GFP-Rb fragments using anti-GFP antibodies co-precipitated LAP2 provided that pocket C was present in the GFP chimeras. Upon redistribution of endogenous lamin A/C and LAP2 into nuclear aggregates by over-expressing dominant negative lamin mutants in tissue culture cells, Rb was also sequestered into these aggregates. In primary skin fibroblasts LAP2 is expressed in a growth dependent manner. Anchorage of hypophosphorylated Rb in the nucleus was weakened significantly in the absence of LAP2. Together, these data suggest that hypophosphorylated Rb is anchored in the nucleus by the interaction of pocket C with LAP2 - lamin A/C complexes.
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