Curriculum Vitae
Research
Interest
There are several areas of activity in our laboratory. One has
been to define the
in vivo
importance of the posttranslational modifications of isoprenylated
proteins. We have used gene-targeted mice to define the
importance of several enzymes that are involved in the processing
of isoprenylated proteins (e.g.,
the Ras proteins and the nuclear lamins). We have shown that the
knockout of an endoprotease gene,
Zmpste24,
prevents the production of mature lamin A from a farnesylated
precursor, prelamin A. In the setting of Zmpste24
deficiency, farnesyl-prelamin A accumulates in cells, resulting in
misshapen nuclei in cultured fibroblasts.
Zmpste24-deficient
mice develop a host of aging-like disease phenotypes that resemble
those in humans with Hutchinson-Gilford progeria syndrome (HGPS),
a precocious aging syndrome associated with the accumulation of a
mutant form of farnesyl-prelamin A. In recent studies, we have
shown that farnesyl-prelamin A is a toxic molecule; reducing
prelamin A levels by 50% eliminates the misshapen nuclei in
cultured cells and completely “cures” all of the aging-like
disease phenotypes in
Zmpste24-deficient
mice. More recently, we found that blocking the farnesylation of
the prelamin A with a farnesyltransferase inhibitor drug reduces
the misshapen nuclei in cultured cells and ameliorates the
aging-like disease phenotypes in
Zmpste24-deficient
mice.
We have extended the “Zmpste24
studies” by creating a gene-targeted mouse model of HGPS. Once
again, we found that a farnesyltransferase inhibitor drug reduces
the misshapen nuclei in HGPS cells and ameliorates the aging-like
disease phenotypes in HGPS mice. These studies suggest that the
farnesyltransferase inhibitor drugs might be useful for the
treatment of humans with progeria.
Another focus in our laboratory has been gene trapping in
embryonic stem cells. Over the past five years, we have led
BayGenomics
— an NHLBI-funded gene-trapping consortium involving investigators
from UCSF and UCLA. BayGenomics uses gene-trapping techniques to
randomly inactivate genes in mouse embryonic stem cells. One can
browse through a list of more than 10,000 “gene-trapped” ES cell
lines on the BayGenomics web site and then obtain knockout ES cell
lines for any of more than 3,000 different mouse genes. We make
all of our ES cell lines freely available to the scientific
community, for the purpose of generating knockout mice.
One of the other goals of BayGenomics is to identify new genes
that are relevant to cardiopulmonary development and disease.
Recently, we used BayGenomics ES cells to create knockout mice
lacking several triglyceride biosynthetic enzymes. These studies
allowed us to define genes responsible for triglyceride synthesis
in mammary epithelium, brown adipose tissue, skin, and cartilage.
Currently, we are studying additional mice to gain a more complete
understanding of the specific roles of different enzymes in lipid
synthesis in vivo.
Representative
Publications
Skarnes WC, von
Melchner H, Wurst W, Hicks G, Nord AS, Cox T, Young SG, Ruiz P,
Soriano P, Tessier-Lavigne M, Conklin BR, Stanford WL, Rossant J;
International Gene Trap Consortium. (2004) A public gene trap
resource for mouse functional genomics. Nat Genet. 36:
543–544.
Beigneux AP, Kosinski C,
Gavino B, Horton JD, Skarnes WC, Young SG. (2004) ATP-citrate
lyase deficiency in the mouse. J Biol Chem. 279:
9557–9564.
Bergo MO, Lieu HD,
Gavino BJ, Ambroziak P, Otto JC, Casey PJ, Walker QM, Young SG.
(2004) On the physiological importance of endoproteolysis of CAAX
proteins: heart-specific RCE1 knockout mice develop a lethal
cardiomyopathy. J Biol Chem. 279: 4729–4736.
Austin CP,
Battey JF, Bradley A, Bucan M, Capecchi M, Collins FS, Dove WF, Duyk
G, Dymecki S, Eppig JT, Grieder FB, Heintz N, Hicks G, Insel TR,
Joyner A, Koller BH, Lloyd KC, Magnuson T, Moore MW, Nagy A, Pollock
JD, Roses AD, Sands AT, Seed B, Skarnes WC, Snoddy J, Soriano P,
Stewart DJ, Stewart F, Stillman B, Varmus H, Varticovski L, Verma
IM, Vogt TF, von Melchner H, Witkowski J, Woychik RP, Wurst W,
Yancopoulos GD, Young SG, Zambrowicz B. (2004) THE
KNOCKOUT MOUSE PROJECT: A Comprehensive Plan for Placing Knockouts
of All Mouse Genes and Associated Phenotype Data into the Public
Domain Nat. Genet. 36:
921–924.
Anant S, Murmu N,
Houchen CW, Mukhopadhyay D, Riehl TE, Young SG, Morrison AR, Stenson
WF, Davidson NO. (2004) Apobec-1 protects intestine from radiation
injury through posttranscriptional regulation of cyclooxygenase-2
expression. Gastroenterology.
127:1139–1149.
Fong
LG, Ng JK, Meta M, Coté N, Yang SH, Burghardt A, Majumdar S, Reue K,
Bergo MO, Young SG. (2004) Heterozygosity for Lmna deficiency
eliminates the progeria-like phenotypes in Zmpste24-deficient
mice. Proc Natl Acad Sci U S A. 101: 18111–18116.
Yang SH,
Shrivastav A, Kosinski C, Sharma RK, Gavino B, Chen M-H, Peters LL,
Chuang P-T, Young SG. (2004) N-Myristoyltransferase 1 is
essential for early mouse development. J. Biol. Chem.
280:
18990–18995.
Richardson
PE, Manchekar M, Dashti N, Jones MK, Beigneux A, Young SG, Harvey
SC, Segrest JP.
(2005) Assembly of lipoprotein particles containing apolipoprotein-B:
structural model for the nascent lipoprotein particle. Biophys J.
88: 2789–2800.
Michaelson D,
Chieu VK, Bergo M, Siletti J, Young S, and Philips M. (2005) Post-prenylation
CAAX Processing is Required for Farnesylated but not
Gernaylgeranylated GTPases. Molec. Biol. Cell.
16:
1606–1616.
Toth JI,
Yang SH, Qiao X, Beigneux AP, Gelb MH, Moulson CL, Miner JH, Young
SG, Fong LG. (2005)
Blocking protein farnesyltransferase improves nuclear shape in
fibroblasts from humans with progeroid syndromes. Proc Natl Acad
Sci USA. 102: 12873–12878.
Schneider M,
Witztum JL, Young SG, Ludwig EH, Miller ER, Tsimikas S, Curtiss LK,
Marcovina SM, Taylor JM, Lawn RM, Innerarity TL, Pitas RE.
(2005) High-level lipoprotein [a] expression in transgenic mice:
evidence for oxidized phospholipids in lipoprotein [a] but not in
low density lipoproteins. J Lipid Res. 46: 769–778.
Steenbergen
R, Nanowski TS, Beigneux A, Kulinski A, Young SG, Vance JE.
(2005) Disruption of the phosphatidylserine decarboxylase gene in
mice causes embryonic lethality and mitochondrial defects. J Biol
Chem. 280: 40032–40040.
Young SG.
(2005) A thematic review series: Lipid modifications of proteins.
J Lipid Res. 46: 2529–2530.
Takahashi K,
Nakagawa M, Young SG, Yamanaka S.
(2005) Differential membrane localization of ERas and Rheb, two Ras-related
proteins involved in the phosphatidylinositol 3-kinase/mTOR pathway.
J Biol Chem. 280: 32768–32774.
Word RA,
Landrum CP, Timmons BC, Young SG, Mahendroo MS.
(2005) Transgene Insertion on Mouse Chromosome 6 Impairs Function of
the Uterine Cervix and Causes Failure of Parturition. Biol Reprod.
73: 1046–1056.
Yang SH,
Bergo MO, Toth JI, Qiao X, Hu Y, Sandoval S, Meta M, Bendale P, Gelb
MH, Young SG, Fong LG.
(2005) Blocking protein farnesyltransferase improves nuclear
blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford
progeria syndrome mutation. Proc Natl Acad Sci USA. 102:
10291–10296.
Winter-Vann
AM, Baron RA, Wong W, dela Cruz J, York JD, Gooden DM, Bergo MO,
Young SG, Toone EJ, Casey PJ.
(2005) A small-molecule inhibitor of isoprenylcysteine carboxyl
methyltransferase with antitumor activity in cancer cells. Proc
Natl Acad Sci USA. 102: 4336–4341.
Young SG, Fong LG,
Michaelis S. (2005) Prelamin A, Zmpste24, misshapen cell nuclei, and
progeria—New evidence suggesting that protein farnesylation could be
important for disease pathogenesis. J Lipid Res. 46:
2531–2558.
Fong LG, Ng JK,
Lammerding J, Vickers TA, Meta M, Coté N, Gavino B, Qiao X, Chang SY,
Young SR, Yang SH, Stewart CL, Lee RT, Bennett CF, Bergo MO, Young
SG. (2006) Prelamin A and lamin A appear to be dispensable:
Implications for the treatment of progeria. J. Clin. Invest.
116: 743–752.
Young SG, Clarke S,
Bergo MO, Philips M, and Fong LG. Genetic approaches for
understanding the physiologic importance of the carboxyl methylation
of isoprenylated proteins. The Enzymes. (In Press)
Svensson A, Casey
PL, Young SG, Bergo MO. Genetic
and Pharmacologic Analyses of the Role of Icmt in Ras Membrane
Association and Function. Methods in Enzymology. (In Press)
Young SG,
Bergo M, and Fong LG. Genetic analyses of Rce1 function in Ras
membrane association and function. Methods in Enzymology. (In
Press)
Fueller F, Bergo
M, Young SG, Aktories K, and Schmidt G. (2006) Endoproteolytic
processing of RhoA by Rce1 is required for the cleavage of RhoA by
Yersinia enterocolitica outer protein T (YOPT). Infection
and Immunity.
74:1712–1217.
Fong LG, Frost D, Meta
M, Qiao X, Yang SH, Coffinier C, and Young SG. (2006) A Protein
Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model
of Progeria. Science. 311: 1621–1623.
Beigneux AP,
Vergnes L, Qiao X, Quatela S, Davis R, Watkins SM, Coleman RA,
Walzem RL, Philips M, Reue K, Young SG. (2006)
Agpat6-a novel lipid biosynthetic gene
required for triacylglycerol production in mammary epithelium.
J. Lipid Res. 47: 734–744.
Vergnes L,
Beigneux AP, Davis R, Watkins SM, Young SG, Reue K. (2006)
Agpat6 deficiency causes subdermal
lipodystrophy and resistance to obesity.
J. Lipid Res. 47: 745–754
Nord AS, Chang PJ,
Conklin BR, Cox AV, Harper CA, Hicks GG, Huang CC, Johns SJ,
Kawamoto M, Liu S, Meng EC, Morris JH, Rossant J, Ruiz P, Skarnes
WC, Soriano P, Stanford WL, Stryke D, von Melchner H, Wurst W,
Yamamura K, Young SG, Babbitt PC, Ferrin TE. (2006)
The International Gene Trap Consortium
Website: a portal to all publicly available gene trap cell lines in
mouse.
Nucleic Acids Res. 34(Database
issue): D642-8.
Xie Y, Newberry
EP, Young SG, Robine S, Hamilton RL, Wong JS, Luo J, Kennedy S,
Davidson NO. (2006) Compensatory
Increase in Hepatic Lipogenesis in Mice with Conditional
Intestine-specific Mttp Deficiency.
J Biol Chem.
281:4075–86.
Huang AS,
Beigneux A, Weil ZM, Kim PM, Molliver ME, Blackshaw S, Nelson RJ,
Young SG, Snyder SH. (2006) D-aspartate regulates melanocortin
formation and function: behavioral alterations in D-aspartate
oxidase-deficient mice. J Neurosci. 26: 2814–2819. |
