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PMID: 2335559 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Isoprenylation is required for the processing of the lamin A precursor.

The Journal of cell biology ·Vol. 110 ·No. 5 ·1990-05-00 ·Pages 1489-99

Beck LA, Hosick TJ, Sinensky M

Abstract

The nuclear lamina proteins, prelamin A, lamin B, and a 70-kD lamina-associated protein, are posttranslationally modified by a metabolite derived from mevalonate. This modification can be inhibited by treatment with (3-R,S)-3-fluoromevalonate, demonstrating that it is isoprenoid in nature. We have examined the association between isoprenoid metabolism and processing of the lamin A precursor in human and hamster cells. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by mevinolin (lovastatin) specifically depletes endogenous isoprenoid pools and inhibits the conversion of prelamin A to lamin A. Prelamin A processing is also blocked by mevalonate starvation of Mev-1, a CHO cell line auxotrophic for mevalonate. Moreover, inhibition of prelamin A processing by mevinolin treatment is rapidly reversed by the addition of exogenous mevalonate. Processing of prelamin A is, therefore, dependent on isoprenoid metabolism. Analysis of the conversion of prelamin A to lamin A by two independent methods, immunoprecipitation and two-dimensional nonequilibrium pH gel electrophoresis, demonstrates that a precursor-product relationship exists between prelamin A and lamin A. Analysis of R,S-[5-3H(N)]mevalonate-labeled cells shows that the rate of turnover of the isoprenoid group from prelamin A is comparable to the rate of conversion of prelamin A to lamin A. These results suggest that during the proteolytic maturation of prelamin A, the isoprenylated moiety is lost. A significant difference between prelamin A processing, and that of p21ras and the B-type lamins that undergo isoprenylation-dependent proteolytic maturation, is that the mature form of lamin A is no longer isoprenylated.

MeSH Terms
Amino Acid Sequence Animals Carbon Radioisotopes Cell Nucleus/ultrastructure Cells, Cultured Electrophoresis, Gel, Two-Dimensional Humans Intermediate Filaments/analysis Kinetics Lamin Type A Lamin Type B Lamins Methionine/metabolism Mevalonic Acid/metabolism Molecular Sequence Data Nuclear Proteins/metabolism Precipitin Tests Protein Precursors/metabolism Protein Processing, Post-Translational/physiology Sulfur Radioisotopes
Chemicals
Carbon Radioisotopes Lamin Type A Lamin Type B Lamins Nuclear Proteins Protein Precursors Sulfur Radioisotopes Methionine Mevalonic Acid
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Beck L A
Eleanor Roosevelt Institute for Cancer Research, Inc., Denver, Colorado 80206.
Hosick T J
Sinensky M
References (55)
55 references, click to expand
  1. Autoimmune response directed against conserved determinants of nuclear envelope proteins in a patient with linear scleroderma.
    Proc Natl Acad Sci U S A. 1983 Jul;80(14):4374-8 PMID: 6192431
  2. Cellular distribution of cholesterogenesis-linked, phosphoisoprenylated proteins in proliferating cells.
    FEBS Lett. 1989 Mar 13;245(1-2):110-6 PMID: 2924914
  3. The conserved carboxy-terminal cysteine of nuclear lamins is essential for lamin association with the nuclear envelope.
    J Cell Biol. 1989 Nov;109(5):2003-11 PMID: 2808518
  4. All ras proteins are polyisoprenylated but only some are palmitoylated.
    Cell. 1989 Jun 30;57(7):1167-77 PMID: 2661017
  5. Immunocytochemical localization of the major polypeptides of the nuclear pore complex-lamina fraction. Interphase and mitotic distribution.
    J Cell Biol. 1978 Nov;79(2 Pt 1):546-66 PMID: 102651
  6. Lamin A is not synthesized as a larger precursor polypeptide.
    Biochem Biophys Res Commun. 1987 Dec 16;149(2):417-23 PMID: 3426582
  7. Evidence for post-translational incorporation of a product of mevalonic acid into Swiss 3T3 cell proteins.
    J Biol Chem. 1984 Aug 25;259(16):10175-80 PMID: 6565705
  8. Nuclear lamina and the structural organization of the nuclear envelope.
    Cold Spring Harb Symp Quant Biol. 1982;46 Pt 2:967-78 PMID: 7049540
  9. The p21 ras C-terminus is required for transformation and membrane association.
    Nature. 1984 Aug 16-22;310(5978):583-6 PMID: 6087162
  10. Modification of nuclear lamin proteins by a mevalonic acid derivative occurs in reticulocyte lysates and requires the cysteine residue of the C-terminal CXXM motif.
    EMBO J. 1989 Dec 20;8(13):4007-13 PMID: 2686979
  11. Prenylated proteins from kidney.
    Biochem Biophys Res Commun. 1986 Aug 29;139(1):209-14 PMID: 3094509
  12. Defective macromolecule biosynthesis and cell-cycle progression in a mammalian cell starved for mevalonate.
    Proc Natl Acad Sci U S A. 1985 May;82(10):3257-61 PMID: 2582409
  13. A fractionated cell-free system for analysis of prophase nuclear disassembly.
    J Cell Biol. 1986 Dec;103(6 Pt 1):2073-81 PMID: 3782291
  14. Isolation and characterization of a mammalian cell mutant defective in 3-hydroxy-3-methylglutaryl coenzyme A synthase.
    J Biol Chem. 1982 Jan 10;257(1):472-6 PMID: 6118375
  15. Structure and activation of the human N-ras gene.
    Cell. 1983 Sep;34(2):581-6 PMID: 6616621
  16. A cell free system to study reassembly of the nuclear envelope at the end of mitosis.
    Cell. 1986 Feb 28;44(4):639-52 PMID: 3948244
  17. The nuclear envelope lamina is reversibly depolymerized during mitosis.
    Cell. 1980 Jan;19(1):277-87 PMID: 7357605
  18. Isolation of nuclear pore complexes in association with a lamina.
    Proc Natl Acad Sci U S A. 1975 Mar;72(3):1007-11 PMID: 1055359
  19. Cell cycle-dependent methyl esterification of lamin B.
    J Biol Chem. 1987 Mar 25;262(9):4303-9 PMID: 3558408
  20. Peptidal Sex Hormones Inducing Conjugation Tube Formation in Compatible Mating-Type Cells of Tremella mesenterica.
    Science. 1981 Jun 26;212(4502):1525-7 PMID: 17790543
  21. The major polypeptides of the nuclear pore complex.
    Exp Cell Res. 1978 Oct 1;116(1):85-102 PMID: 568072
  22. Incorporation of a product of mevalonic acid metabolism into proteins of Chinese hamster ovary cell nuclei.
    J Cell Biol. 1988 Oct;107(4):1307-16 PMID: 3170631
  23. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications.
    Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350-4 PMID: 388439
  24. Biosynthesis and secretion of tremerogen A-10, a polyisoprenyl peptide mating pheromone of Tremella mesenterica.
    Eur J Biochem. 1985 Mar 15;147(3):489-93 PMID: 4038940
  25. Analysis of regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in a somatic cell mutant auxotrophic for mevalonate.
    J Biol Chem. 1982 Jul 10;257(13):7284-6 PMID: 7085625
  26. Genes in S. cerevisiae encoding proteins with domains homologous to the mammalian ras proteins.
    Cell. 1984 Mar;36(3):607-12 PMID: 6365329
  27. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.
    Proc Natl Acad Sci U S A. 1980 Jul;77(7):3957-61 PMID: 6933445
  28. Genetics of somatic mammalian cells. IX. Quantitation of mutagenesis by physical and chemical agents.
    J Cell Physiol. 1969 Dec;74(3):245-58 PMID: 5390857
  29. CLONAL GROWTH OF MAMMALIAN CELLS IN A CHEMICALLY DEFINED, SYNTHETIC MEDIUM.
    Proc Natl Acad Sci U S A. 1965 Feb;53:288-93 PMID: 14294058
  30. Lamin B from rat liver nuclei exists both as a lamina protein and as an intrinsic membrane protein.
    J Biol Chem. 1984 Mar 10;259(5):2693-6 PMID: 6698987
  31. Human lamin B contains a farnesylated cysteine residue.
    J Biol Chem. 1989 Dec 5;264(34):20422-9 PMID: 2684976
  32. Evidence for modification of lamin B by a product of mevalonic acid.
    J Biol Chem. 1988 May 5;263(13):5997-6000 PMID: 3283116
  33. Biogenesis of the nuclear lamina: in vivo synthesis and processing of nuclear protein precursors.
    Proc Natl Acad Sci U S A. 1986 Apr;83(7):2096-9 PMID: 3515346
  34. The nuclear lamins. A multigene family of proteins in evolution and differentiation.
    Exp Cell Res. 1986 Jan;162(1):1-10 PMID: 2415378
  35. cDNA sequencing of nuclear lamins A and C reveals primary and secondary structural homology to intermediate filament proteins.
    Proc Natl Acad Sci U S A. 1986 Sep;83(17):6450-4 PMID: 3462705
  36. Expression of specific high capacity mevalonate transport in a Chinese hamster cell variant.
    J Biol Chem. 1987 Feb 15;262(5):1996-2004 PMID: 3643925
  37. The a-factor pheromone of Saccharomyces cerevisiae is essential for mating.
    Mol Cell Biol. 1988 Mar;8(3):1309-18 PMID: 3285180
  38. p21ras is modified by a farnesyl isoprenoid.
    Proc Natl Acad Sci U S A. 1989 Nov;86(21):8323-7 PMID: 2682646
  39. Phosphorylation of the nuclear lamins during interphase and mitosis.
    J Biol Chem. 1985 Jan 10;260(1):624-32 PMID: 3965465
  40. Homologies in both primary and secondary structure between nuclear envelope and intermediate filament proteins.
    Nature. 1986 Feb 6-12;319(6053):463-8 PMID: 3453101
  41. George Otto Gey. (1899-1970). The HeLa cell and a reappraisal of its origin.
    Obstet Gynecol. 1971 Dec;38(6):945-9 PMID: 4942173
  42. Organization and modulation of nuclear lamina structure.
    J Cell Sci Suppl. 1984;1:137-60 PMID: 6597817
  43. Mechanism of the inhibition of cholesterol biosynthesis by 6-fluoromevalonate.
    Biochem J. 1985 Apr 1;227(1):247-54 PMID: 2986604
  44. The CaaX motif of lamin A functions in conjunction with the nuclear localization signal to target assembly to the nuclear envelope.
    Cell. 1989 Dec 22;59(6):969-77 PMID: 2557160
  45. A modified procedure for the isolation of a pore complex-lamina fraction from rat liver nuclei.
    J Cell Biol. 1976 Sep;70(3):581-91 PMID: 986398
  46. Structure of Saccharomyces cerevisiae mating hormone a-factor. Identification of S-farnesyl cysteine as a structural component.
    J Biol Chem. 1988 Dec 5;263(34):18236-40 PMID: 3056940
  47. Maturation of nuclear lamin A involves a specific carboxy-terminal trimming, which removes the polyisoprenylation site from the precursor; implications for the structure of the nuclear lamina.
    FEBS Lett. 1989 Nov 6;257(2):411-4 PMID: 2583287
  48. Functional organization of the nuclear envelope.
    Annu Rev Cell Biol. 1988;4:335-74 PMID: 2461721
  49. Induction of early mitotic events in a cell-free system.
    Cell. 1985 May;41(1):165-75 PMID: 3888406
  50. Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans.
    Science. 1989 Jul 28;245(4916):379-85 PMID: 2569235
  51. Isoprenylated proteins in cultured cells: subcellular distribution and changes related to altered morphology and growth arrest induced by mevalonate deprivation.
    J Cell Physiol. 1987 Dec;133(3):471-81 PMID: 3693410
  52. Post-translational processing of p21ras is two-step and involves carboxyl-methylation and carboxy-terminal proteolysis.
    EMBO J. 1989 Apr;8(4):1093-8 PMID: 2663468
  53. Posttranslational modification of the Ha-ras oncogene protein: evidence for a third class of protein carboxyl methyltransferases.
    Proc Natl Acad Sci U S A. 1988 Jul;85(13):4643-7 PMID: 3290900
  54. Post-translational isoprenylation of cellular proteins is altered in response to mevalonate availability.
    J Biol Chem. 1989 Jun 15;264(17):9945-52 PMID: 2722887
  55. Identification of distinct messenger RNAs for nuclear lamin C and a putative precursor of nuclear lamin A.
    J Cell Biol. 1984 Mar;98(3):980-5 PMID: 6699095
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.110.5.1489
Published
1990-05-00
Pages
1489-99
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2200179
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.110.5.1489 PMC Full Text View journal details
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