It is well-established that some product(s) or metabolite(s) of mevalonate is (are) critical for growth of mammalian cells. In the search for this (these) compound(s) it seems meaningful to distinguish between compounds needed for cell cycle progression in proliferating cells and compounds needed for growth activation of arrested cells. By using time-lapse video recording we have studied the possible regulatory role of cholesterol, dolichol and mevalonate in the cell cycle of human diploid fibroblasts (HDF). HDF, which are serum-dependent, were rapidly growth-arrested in the first part of G1 upon removal of serum factors. They also responded to mevinolin (an HMG CoA reductase inhibitor) by a similar G1-block, indicating that a mevalonate-derived product is involved in the G1-located cell cycle control of HDF. Interestingly, dolichol counteracted the G1-block caused by both types of treatment. Hence, the early G1-cells could traverse the remainder of the cell cycle and divide despite depletion of serum or mevalonate. We also demonstrated that addition of dolichol resulted in a significant decrease in the rate of protein degradation. This protein stabilizing effect may constitute the mechanism by which dolichol delays the G1-arrest of HDF.
REFERENCES
Adair
W. L.
Jr., Cafmeyer
N.
(1987
). Cell cycle dependence of dolichyl phosphate biosynthesis.
Arch. Biochem. Biophys
258
, 491
–497
Baisch
H.
, Gödhe
W.
, Linden
W.
(1975
). Analysis of PCP-data to determine the fraction of cells in the various phases of cell cycle.
Radiat. Environ. Biophys
12
, 31
–39
Bradford
M. M.
(1976
). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
Anal. Biochem
72
, 248
–254
Brown
M. S.
, Goldstein
J. L.
(1980
). Multivalent feedback regulation of HMG CoA reductase: A control mechanism coordinating isoprenoid synthesis and cell growth.
J. Lipid Res
21
, 505
–517
Carpenter
G.
, Cohen
S.
(1977
). Influence of lectins on the binding of125 I-labelled EGF to human fibroblasts.
Biochem. Biophys. Res. Commun
79
, 545
–552
Carson
D. D.
, Lennarz
W. J.
(1981
). Relationship of dolichol synthesis to glycoprotein synthesis during embryonic development.
J. Biol. Chem
256
, 4679
–4686
Casey
P. L.
, Solski
P.A.
, Der
C. J.
, Buss
J. E.
(1989
). p21ras is modified by a farnesyl isoprenoid.
Proc. Nat. Acad. Sci. U.S.A
86
, 8323
–8327
Colchini
K.
, Norman
J.
, Bohman
R.
, Kurtz
I.
(1989
). Induction of hypertrophy in cultured proximal tubule cells by extracellular NH4 Cl.
J. Clin. Invest
84
, 1767
–1779
DeClue
J. E.
, Vass
W. C.
, Papageorge
A. G.
, Lowy
D. R.
, Willumsen
B. M.
(1991
). Inhibition of cell growth is independent of ras function.
Cancer Res
51
, 712
–717
Defendi
V.
, Manson
L. A.
(1963
). Analysis of the life cycle in mammalian cells.
Nature
198
, 356
–361
Doyle
J. W.
, Kandutsch
A. A.
(1988
). Requirement for mevalonate in cycling cells: Quantitative and temporal aspects.
J. Cell. Physiol
137
, 137
–140
Endo
A.
, Hasumi
K.
(1989
). Biomedical aspect of HMG CoA reductase inhibitors.
Advan Enzyme Reg
27
, 53
–64
Fairbanks
K. P.
, Witte
L. D.
, Goodman
D. S.
(1984
). Relationship between mevalonate and mitogenesis in human fibroblasts stimulated with platelet-derived growth factor.
J. Biol. Chem
259
, 1546
–1551
Glomset
J. A.
, Gelb
M. H.
, Farnsworth
C. C.
(1990
). Prenylated proteins in eukaryotic cells: A new type of membrane anchor.
Trends Biochem. Sci
15
, 139
–142
Goldstein
J. L.
, Brown
M. S.
(1990
). Regulation of the mevalonate pathway.
Nature
343
, 425
–430
Habenicht
A. J. R.
, Glomset
J. A.
, Ross
R. J.
(1980
). Relationship of cholesterol and mevalonic acid to the cell cycle in smooth muscle and Swiss 3T3-cells stimulated by platelet derived growth factor.
J. Biol. Chem
255
, 4134
–5140
Harrington
M. A.
, Pledger
W. J.
(1987
). Platelet-derived growth factor stimulated mechanisms of glucosamine incorporation.
Amer. J. Physiol
253
, 567
–.Jakobisiak
M.
, Bruno
S.
, Skierski
J. S.
, Darzynkiewicz
Z.
(1991
). Cell cycle-specific effects of lovastatin.
Proc. Nat. Acad. Sci. U.S.A
88
, 3628
–3632
Kabakoff
B. D.
, Doyle
J. W.
, Kandutsch
A. A.
(1990
). Relationships among dolichyl phosphate, glycoprotein synthesis, and cell culture growth.
Arch. Biochem. Biophys
276
, 382
–389
Kelly
K.
, Cochran
B. H.
, Stiles
C. D.
, Leder
P.
(1983
). Cell cycle specific regulation of the c-myc gene by lymphocyte mitogens and platelet derived growth factor.
Cell
35
, 603
–610
Keyomarsi
K.
, Sandoval
L.
, Band
V.
, Pardee
A. B.
(1991
). Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin.
Cancer Res
51
, 3602
–3609
Knudsen
M. J.
, Troy
F. A.
(1989
). Nuclear magnetic resonance studies of polyisoprenols in model membranes.
Chem. Phys. Lipids
51
, 205
–212
Langan
T. J.
, Volpe
J. J.
(1987
). Cell cycle specific requirement for mevalonate, but not cholesterol for DNA synthesis in glial primary cultures.
J. Neurochem
49
, 513
–521
Larsson
O.
(1985
). Commitment events in early G1. Requirement for dolichol dependent glycoproteins.
Cell Biol. Int. Rep
9
, 627
–636
Larsson
O.
, Zetterberg
A.
(1986
). Effects of 25-hydroxycholesterol, cholesterol and isoprenoid derivatives on the G1 -progression in Swiss 3T3-cells.
J. Cell. Physiol
129
, 94
–102
Lockwood
T. D.
, Minassian
I. A.
, Roux
L.
(1982
). Protein turnover and proliferation.
Biochem. J
206
, 239
–249
Macieira-Coelho
A.
, Ponten
J.
, Philipson
L.
(1966
). The division cycle and RNA synthesis in diploid cells at different passage levels in vitro.
Exp. Cell Res
92
, 673
–684
Moorehead
P. S.
, Defendi
V.
(1963
). Asynchrony of DNA synthesis in chromosomes of human diploid fibroblasts.
J. Cell Biol
16
, 202
–209
Perkins
S. L.
, Ledin
S. F.
, Stubbs
J. D.
(1982
). Linkage of the isoprenoid synthesis pathway with induction of DNA synthesis in mouse lymphocytes. Effects of compactin on mitogen induced lymphocytes in serum-free medium.
Biochim. Biophys. Acta
711
, 83
–89
Quesney-Huneeus
V.
, Wiley
M. A.
, Siperstein
M. D.
(1980
). Isopentenyladenine as a mediator of mevalonate-regulated DNA replication.
Proc. Nat. Acad. Sci. U.S.A
77
, 5842
–5846
Rip
J. W.
, Rupar
C. A.
, Ravi
K.
, Caroll
K. K.
(1985
). Distribution, metabolism and function of dolichol and polyprenols.
Prog. Lipid Res
24
, 269
–309
deRopp
J. S.
, Troy
F. A.
(1985
). 2 H-NMR investigation of the organization and dynamics of polyisoprenols in membranes.
J. Biol. Chem
260
, 15669
–15674
Rossow
P. W.
, Riddle
V. G. H.
, Pardee
A. B.
(1979
). Synthesis of labile, serum-dependent protein in early G1 controls animal cell growth.
Proc. Nat. Acad. Sci. U.S.A
76
, 4446
–4450
Schafer
W. R.
, Kim
R.
, Sterne
R.
, Thorne
J.
, Kim
S.-H.
, Rine
J.
(1989
). Genetic and pharmacological suppression of oncogenic mutations in RAS genes of yeast and humans.
Science
245
, 379
–385
Schmidt
R. A.
, Schneider
C. J.
, Glomset
J. A.
(1984
). Evidence for post-translational incorporation of a product of mevalonic acid into Swiss 3T3 cell proteins.
J. Biol. Chem
259
, 10175
–10180
Shilo
B.
, Riddle
V. G. H.
, Pardee
A. B.
(1979
). Protein turnover and cell cycle initiation in yeast.
Exp. Cell Res
123
, 221
–227
Sinensky
M.
, Logel
J.
(1985
). Defective macromolecule biosynthesis and cell cycle progression in a mammalian cell starved for mevalonate.
Proc. Nat. Acad. Sci. U.S.A
82
, 3257
–3261
Siperstein
M. D.
(1984
). Role of cholesterologenesis and isoprenoid synthesis in DNA replication and cell growth.
J. Lipid Res
25
, 1462
–1468
Stein
G. H.
, Atkins
L.
(1986
). Membrane associated inhibitor of DNA synthesis in senescent human diploid fibroblasts. Characterization and comparison to quiescent cell inhibitor.
Proc. Nat. Acad. Sci. U.S.A
83
, 9030
–9034
Valtersson
C.
, van Duijn
G.
, Verkleij
A. J.
, Chojnacki
T.
, deKruijff
B.
, Dallner
G.
(1985
). The influence of dolichol, dolichol esters, and dolichyl phosphate on phospholipid polymorphism and fluidity in model membranes.
J. Biol. Chem
260
, 2742
–2751
Yachnin
S.
(1982
). Mevalonic acid as an initiator of cell growth: Studies using human lymphocytes and inhibitors of endogenous mevalonate biosynthesis.
Oncodev. Biol. Med
3
, 111
–123
Zetterberg
A.
, Larsson
O.
(1985
). Kinetic analysis of regulatory events leading to proliferation or quiescence of Swiss 3T3-cells.
Proc. Nat. Acad. Sci. U.S.A
82
, 5365
–5369
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