Ribosome Biogenesis as novel p53-dependent cell cycle
checkpoint
It has long been known that production
of the protein synthesis machinery, the ribosomes, is
coordinated with cell growth and proliferation. However,
the mechanism by which this coordination occurs has
been unclear. We have recently identified a novel nucleolar
protein, Bop1, which acts as an essential component
of the mammalian rRNA processing machinery. Inducible
expression of a dominant negative inhibitor of Bop1
leads to blockade of 28S and 5.8S rRNA maturation and
60S ribosome biogenesis, and unexpectedly, a powerful
cell cycle arrest at G1. Remarkably, this cell cycle
arrest is dependent on the activities of p53 in mammalian
cells, and is not observed with a similar rRNA processing
block in yeast. Thus, these findings indicate the presence
of a mammalian-specific, p53-mediated surveillance mechanism
that monitors nucleolar pre-ribosome assembly as a novel
cell cycle checkpoint. Current research focuses on understanding
the mechanism of mammalian ribosome assembly, and how
it is monitored by p53 as a checkpoint for cell cycle
progression.
Selected Publictions:
Chen, N., Chen, C.-C., and Lau, L.F. (2000) Adhesion
of human skin fibroblasts to Cyr61 is mediated through
integrin alpha6beta1 and cell surface heparan sulfate
proteoglycans. J. Biol. Chem. 275: 24953-24961.[ABSTRACT]
Strezoska Z., Pestov, D.G., and Lau, L.F. (2000) Bop1
is a mouse WD40-repeat nuclear protein involved in 28S
and 5.8S rRNA processing and 60S ribosome biogenesis.
Mol. Cell. Biol. 20: 5516-5528.[ABSTRACT]
Li, Y. and Lau, L.F. (2000) An inducible episomal expression
system for exogenous genes in primate cells. BioTechniques
28: 577-581.[ABSTRACT]
Grotendorst, G.R., Lau, L.F., and Perbal, B. (2000)
CCN proteins are functionally distinct from and should
not be considered members of the IGFBP superfamily.
Endocrinology 141, 2254-2256.
Chung, K.C., Kim, S.M., Rhang, S., Lau, L.F., Gomes,
I., and Ahn, Y.S. (2000) Expression of immediate early
gene pip92 during anisomycin-induced cell death is mediated
by the JNK- and p38-dependent activation of elk1. Eur
J Biochem 267, 4676-84.[ABSTRACT]
Stocco, C.O., Zhong, L., Sugimoto, Y., Frasor, J., Ichikawa,
A., Lau, L.F., and Gibori, G. (2000) Prostaglandin F2?-induced
expression of 20?-HSD gene in the corpus luteum involves
Nur77. J. Biol. Chem. 275: 37202-37211[ABSTRACT]
Chen, C.-C., Chen, N., and Lau, L.F. (2001) The angiogenic
inducers CYR61 and CTGF mediate adhesive signaling in
primary human fibroblasts. J. Biol. Chem. 276: 10443-10452.[ABSTRACT]
Latinkic, B.V., Mo, F.-E, Greenspan, J.A., Copeland,
N.G., Gilbert, D.J., Jenkins, N.A., Ross, S.R., and
Lau, L.F. (2001) Promoter function of the angiogenic
inducer Cyr61 gene in transgenic mice: tissue specificity,
inducibility during wound healing, and role of the serum
response element. Endocrinology 142: 2549-2557.[ABSTRACT]
Pestov, D.G., Strezoska, Z., and Lau, L.F. (2001) Evidence
of p53-dependent cross-talk between ribosome biogenesis
and the cell cycle: effects of the nucleolar protein
Bop1 on G1/S transition. Mol. Cell. Biol. 21: 4246-4255.
[ABSTRACT]
Grzeszkiewicz, T.M., Kirschling, D.J., Chen, N., and
Lau, L.F. (2001) The angiogenic inducer CYR61 stimulates
human skin fibroblast migration through integrin ?v?5
and enhances mitogenesis through integrin ?v?3, independent
of its carboxyl-terminal domain. J. Biol. Chem., 276:
21943- 21950.[ABSTRACT]
Pestov, D.G., Stockelman, M.G., Strezoska, Z., and Lau,
L.F. (2001) ERB1, yeast homolog of the mammalian Bop1,
is an essential gene required for maturation of the
25S and 5.8S ribosomal RNAs. Nucleic Acids Res. 29:
3621-3630.[ABSTRACT]
Chen, C.-C., Mo, F.-E, and Lau, L.F. (2001) The angiogenic
factor Cyr61 activates a genetic program for wound healing
in primary human skin fibroblasts. J. Biol. Chem. 276:
47329-47337.[ABSTRACT]
Lau, L.F. (2001) The CCN gene family. The Encyclopedia
of Molecular Medicine. Vol. 1, pp.515-517. John Wiley
& Sons, New York, New York.
Stocco, C.O., Lau, L.F., and Gibori, G. (2002) A calcium/calmodulin
dependent activation of ERK1/2 mediates JunD phosphorylation
and induction of Nur77 and 20?-hsd genes by PGF2? in
ovarian cells. J. Biol. Chem. 277: 3293-3302.[ABSTRACT]
Grzeszkiewicz, T.M., Lindner, V., Chen, N., Lam, S.C.-T.,
and Lau, L.F. (2002) CYR61 is upregulated during vascular
injury and stimulates vascular smooth muscle cell adhesion
and chemotaxis through integrin ?6?1 and cell surface
heparan sulfate proteoglycans. Endocrinology, 143: 1441-1450.[ABSTRACT]
Schober, J.M., Chen, N., Grzeszkiewicz, T.G., Emeson,
E.E., Ugarova, T.P., Ye, R., Lau, L.F., and Lam, S.C.-T.
(2002) Identification of integrin ?M?2 as an adhesion
receptor on peripheral blood monocytes for Cyr61 and
connective tissue growth factor, angiogenic factors
expressed in atherosclerotic lesions. Blood 99: 4457-4465.[ABSTRACT]
Strezoska, Z, Pestov, D.G., and Lau, L.F. (2002) Functional
inactivation of the mouse nucleolar protein Bop1 inhibits
multiple steps in pre-rRNA processing and blocks cell
cycle progression. J. Biol. Chem. 277: 29617-25.[ABSTRACT]
Leu, S.J., Lam, S.C.-T., and Lau, L.F. (2002) Pro-angiogenic
activities of CYR61 (CCN1) mediated through integrins
?v?3 and ?6?1 in human umbilical vein endothelial cells.
J. Biol. Chem. 277: 46248-55.[ABSTRACT]
Mo, F.-E, Muntean, A.G., Chen, C.-C., Stolz, D.B., Watkins,
S.C., and Lau, L.F. (2002) CYR61 (CCN1) is essential
for placental development and vascular integrity. Mol.
Cell. Biol. 22: 8709-8720.[ABSTRACT]
Perbal, B., Brigstock, D.R., and Lau, L.F. (2003) Report
on the second international workshop on the CCN family
of genes. Molecular Pathology 56: 80-85.[ABSTRACT]
Brigstock, D.R., Goldschmeding, R., Katsube, K.-I.,
Lam, S.C.-T., Lau, L.F., Lyons, K., Naus, C., Perbal,
B., Riser, B., Takigawa, M., and Yeger, H. (2003) Proposal
for a unified CCN nomenclature. Molecular Pathology
56:127-128.[ABSTRACT]
Kim., K.H., Min, Y.K., Baik, J.-H., Lau, L.F., Chaqour,
B., and Chung, K.C. (2003) Expression of angiogenic
factor Cyr61 during neuronal cell death via the activation
of c-Jun N-terminal kinase and serum response factor.
J. Biol. Chem. 278: 13847-54.[ABSTRACT]
Latinkic, B.V., S. Mercurio, B. Bennett, E. Hirst, Q.
Xu, L.F. Lau, T,J. Mohun and J. C. Smith (2003) Xenopus
cyr61 regulates gastrulation movements and modulates
Wnt signalling. Development, 130: 2429-2441.[ABSTRACT]
Lin, C., Leu, S.-J., Chen, N., Tebeau, C.M., Lin, S.-X.,
Yeung, C.-Y., and Lau, L.F. (2003) CCN3 (NOV) is a novel
angiogenic regulator of the CCN protein family. J. Biol.
Chem. 278: 24200-24208.[ABSTRACT]
Schober, J. M., Ugarova, T.P., Lau, L.F., and Lam, S.C.-T.
(2003)Identification of a novel ?M?2 binding site in
CCN1 (CYR61), a matricellular protein expressed in healing
wounds and atherosclerotic lesions. J. Biol. Chem. 278,
25808-25815.[ABSTRACT]
Leu, S.-J., Liu, Y., Lam., S.C.-T., and Lau, L.F. (2003)
Identification of a novel integrin ?6?1 binding site
in the angiogenic inducer CCN1 (CYR61) J. Biol. Chem.
278, 33801-33808.[ABSTRACT]
Henning, D., So, R.B., Jin, R., Lau, L.F., and Valdez,
B.C. (2003) Links Silencing of RNA helicase II/Gua inhibits
mammalian ribosomal RNA production. J. Biol. Chem. 278,
52307-52314.[ABSTRACT]
Zhang, W., Chuang, Y.J., Swanson, R., Li, J., Leung,
L., Lau, L.F., and Olson, S.T. (2004) Anti-angiogenic
antithrombin downregulates the expression of the pro-angiogenic
heparan sulfate proteoglycan, perlecan, in endothelial
cells. Blood 103, 1185-91.[ABSTRACT]
Lapik, Y.R. Fernandes, C.J., Lau, L.F., and Pestov,
D.G. (2004) Physical and functional interaction between
Pes1 and Bop1 in mammalian ribosome biogenesis. Molecular
Cell 15, 17-29.[ABSTRACT]
Lin, C.G., Chen, C.C., Leu, S.J., Grzeszkiewicz,
T.M., and Lau, L.F. (2005) Integrin-dependent Functions
of the Angiogenic Inducer NOV (CCN3): implication in
wound healing. J Biol Chem. 280, 8229-8237.[ABSTRACT]
Zhang, W., Swanson, R., Izaguirre,
G., Xiong, Y., Lau, L.F., and Olson, S.T. (2005) The
heparin binding site of antithrombin is crucial for
antiangiogenic activity. Blood 106, 1621-8.[ABSTRACT]
Jin, Y., Kim, H.P.,
Ifedgbo, E., Lau, L.F., and Chio, A.M. (2005) Cyr61
Protects against Hyperoxia-Induced Cell Death via Akt
Pathway in Pulmonary Epithelial Cells. Am J. Respir.
Cell Mol Biol. 33:297-302.[ABSTRACT]
Lau, L.F. and Lam,
S.C.-T. (2005) Integrin-mediated CCN functions. In "CCN
proteins: a new family of cell growth regulators,"
B. Perbal and M. Takigawa, Editors. Imperial College
Press, Uk. pp. 61-79.
Todorovic, V., Chen,
C.-C., Hay, N., and Lau, L.F. (2005) The matrix protein
CCN1 (CYR61) induces apoptosis in fibroblasts. J. Cell
Biol. 171: 559-568. [ABSTRACT]
[JCB
Highlight]
Former Graduate
Students
[Ian
J. Davis] M.D. Ph.D., Instructor, Dana-Farber Cancer
Institute
[Branko
V. Latinkic] Ph.D., Lecturer, Cardiff University,
UK
[Shr-Jeng
Leu] PhD, Assistant Professor, National Yang Ming
University, Taiwan
[Timothy
P. Obrien] Ph.D., Associate Professor, Cornell University
[George
P. Yang] M.D., Ph.D., Assistant Professor, Stanford
University
[Jeong
Kyo Yoon] Ph.D., Principal Investigator, Maine Medical
Center Research Institute
|
