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.