John Sedivy is recognized for his efforts in mammalian cell genetics, having developed and pioneered methods for gene targeting of somatic cells. In 1995 his laboratory isolated the first viable gene knockout of the Myc oncogene, and in 1997 the first homozygous gene knockout in a normal human cell. Part of his research program continues to investigate cell cycle regulation in cancer. Since 1998 his research has also focused on the biology of human aging at the cellular level. These projects currently investigate how telomere shortening as well as telomere-independent stresses cause cellular senescence.

Biography

Professor John Sedivy joined the Brown Faculty in 1996 and is a member and Chair of the Department of Molecular Biology, Cell Biology and Biochemistry. He obtained his PhD from Harvard in 1985, and subsequently trained with the Nobel Laureate Philip Sharp at the MIT Center for Cancer Research. He started his independent research career at Yale University in 1988.

John Sedivy is recognized for his efforts in mammalian genetics, having developed and pioneered methods for gene targeting of somatic cells. His research on cell cycle regulation and signal transduction, focusing on the Myc oncogene, has been continuously funded by the NIH since 1989. In 1995 his laboratory isolated the first viable gene knockouts of the c-myc oncogene, and these cell lines have become the premier model system in the Myc field. In 1997 his laboratory succeeded in isolating the first homozygous gene knockout in a normal human cell. Since 1998 his laboratory has pursued, in addition to the Myc project, studies of human replicative senescence (in vitro cell aging).

In addition to writing the first comprehensive book on gene targeting in 1992, John Sedivy has published over 90 original articles. He has served on numerous study sections and advisory committees at the NIH, the American Cancer Society, and the US Army Breast Cancer Initiative. He has consulted extensively on the genetic manipulation of mammalian cells to the biotech industry, including Biogen, Eli Lilly & Co., Abbott Laboratories, and Millenium Pharmaceuticals.

In 2000 John Sedivy became the Principal Investigator of a Center of Biomedical Research Excellence (COBRE) award from the National Center for Research Resources (NIH), an award that to date has brought over $ 22 million to Brown University over a period of 10 years. The COBRE award has been used to establish a Mouse Knockout and Transgenic Core Facility, a Genomics and Bioinformatics Core Facility, and to fund numerous pilot projects in the Division of Biology and Medicine. Most recently, John Sedivy has spearheaded the establishment of a Center for Genomics and Proteomics at Brown University, and the development of new biomedical research space in the Jewelry District of Providence.

Institutions

BU

Research Description

The Sedivy laboratory is funded by two major grants: "Genetic Studies of c-Myc Gene Function in the Cell Cycle" (NIH GM41690), and "Mechanisms of Replicative Senescence in Human Cells" (NIH AG16694). The key objectives of each project are outlined below.

Genetic Studies of c-Myc Gene Function in the Cell Cycle

The goal of this project is to answer the question: How does the c-myc protooncogene regulate cellular proliferation? The c-Myc protein is a transcription factor, and a large number of genes have been proposed to be targets of its regulation. c-Myc has been implicated in the control of cellular proliferation, differentiation, and programmed cell death, but the mechanisms by which it exerts its activity on the cellular machinery are complex and not well understood. Our fascination with c-Myc stems not only from our interest in understanding basic molecular regulatory mechanisms, but also because the deregulation of c-Myc activity is associated with a wide range of human cancers. A genetic analysis can often lead to profound insights into molecular mechanisms, and the construction of knockout mice can be especially powerful. Unfortunately, the c-myc knockout mouse, because of its early embryonic lethality, did not yield insights into either cellular or molecular phenotypes. All attempts to recover c-myc -/- cells from homozygous embryos have been frustrated by the outgrowth of cells that express one of the other Myc family members. To overcome this problem, we used gene targeting to eliminate c-myc expression in a fibroblast cell line shown not to express the other family members. These knockout cells are the first experimental system in which c-myc loss-of-function phenotypes can be thoroughly investigated. The c-myc -/- cells are viable but display profound cell cycle defects. We have initiated a systematic molecular analysis of known cell cycle regulators in the c-myc -/- cells. Our new insights to date are: 1) loss of c-myc affects progression through both the G1 and G2 phases of the cell cycle; 2) the activity of all cyclin-Cdk complexes is affected; 3) the earliest and most prominent defect is an impairment in the activation of cyclin D-Ddk4/6 complexes; 4) c-Myc affects multiple points in the cell cycle, both before and after the restriction point; and 5) loss of c-Myc has profound effects on the accumulation of cellular mass (cell growth). Our objective is to build on these results to fully elucidate how c-Myc regulates transition through the cell cycle. We are currently working towards constructing homozygous c-myc knockouts in human cells, isolating new c-Myc target genes by a combination of microarray expression profiling and chromatin immunoprecipitation, defining the biochemical lesions in G1 and G2 cell cycle mechanisms that result from loss of c-Myc activity, and genetically testing the physiological relevance of the observed biochemical lesions.

Mechanisms of Replicative Senescence in Human Cells

Two fundamentally different aging phenomena have been described at the cellular level: 1) the gradual decline of life processes in postmitotic cells, and 2) the decline and eventual complete cessation of cell division observed in most replicating cell lineages. The former is measured in simple chronological time, and comes into play during the aging of postmitotic adult organisms, such as the nematode, or during the aging of largely postmitotic tissues, such as the brain or muscle in more complex organisms. In contrast, finite replicative lifespan, often referred to as 'cellular replicative senescence', is measured in terms of cell divisions rather than chronological time. The current consensus is that both postmitotic and replicative aging processes are causally related to the aging of humans. The topic of this research project is the molecular mechanism of replicative aging processes, specifically, the molecular machine that actually executes and maintains senescence. The major tool is targeted homologous recombination (gene targeting), which is being performed in normal (nonimmortalized) fibroblastic human cell strains. The targets of gene targeting are the following genes: the tumor suppressors p53 and retinoblastoma (Rb), and the Cdk kinase inhibitors p16INK4A, p19ARF, and p21CIP1/WAF1. The objective is to ablate gene action and subsequently investigate the resultant senescence phenotypes on both the cellular and molecular levels. This direct interventive approach is expected to reveal the functionally relevant components of the molecular senescence machine. The project is based on a model which predicts that the molecular machine that establishes senescence is composed of components that also play roles in cell cycle control during the normal proliferative lifespan of the cell, specifically, the p53-p21 and p16-Rb pathways. All experiments are being performed in normal human cells grown in in vitro cell culture. This is because a large body of evidence indicates that the regulation of replicative senescence mechanisms is significantly different in humans and in rodents. Therefore, due to the ethical unacceptability of experimentally altering the human germ line, and the limited utility of the rodent model to address the specific issues under investigation, the whole-organism transgenic route is not appropriate and the experimental model has been confined to human somatic cell culture.

Awards

1974 Ontario Scholar
1981 Ryan Foundation Fellow
1989 March of Dimes Basil O'Connor Starter Scholar
1990 Presidential Young Investigator
1991 Andrew Mellon Award

Affiliations

1986– American Association for the Advancement of Science (AAAS), Member
1990– American Society for Microbiology (ASM), Member
1990– Genetics Society of America (GSA), Member
1993– American Association for Cancer Research (AACR), Member
2002– American Society for Biochemistry and Molecular Biology (ASBMB), Member
1994–2001 US Army Breast Cancer Initiative, Member, Scientific Advisory Committee, MBG Study Sections
1996–2001 American Cancer Society, Member, Peer Review Committee, DDC Study Section
1998– Organizer, Colloquium on the Biology of Human Aging, Brown University
2000–2003 National Institutes of Health, Member, Scientific Review Group, CDF-2 Study Section
2001–2004 Editor, Journal of Molecular Medicine
2001– Advanced Cell Technology, Inc., Worcester, MA, Scientific Advisory Board Member
2001– Biolog, Inc., Hayward, CA, Scientific Advisory Board Member
2002– Editor, The Aging Cell
2002 Organizer, Banbury Center Conference on Cellular Immortalization, Cold Spring Harbor, NY
2003– Editor, Experimental Cell Research
2003– National Institutes of Health, Member, Scientific Review Group, CMAD Study Section

Funded Research

ONGOING RESEARCH SUPPORT

2 R01 GM41690-17, Sedivy, JM (PI) 07/01/2003-06/30/2007
NIH/NIGMS
Genetic studies of c-myc gene function in the cell cycle
The major goal of this project is to investigate the cell cycle phenotypes of c-myc knockout cells and to clone genes regulated by c-myc.
Role: PI

2 R01 AG16694-07, Sedivy, JM (PI) 04/01/2004-03/30/2009
NIH/NIA
Mechanisms of replicative senescence in human cells
The major goal of this project is to use gene targeting to investigate the roles of the p16INK4A, p19ARF, p53 and Rb genes in replicative senescence in human cells.
Role: PI

2 P20 RR15578-06, Sedivy, JM (PI) 07/01/2005-4/30/2010
NIH/NCRR
Center for Cancer Signaling Networks
This award funds several interdiciplinary projects and core facilities in a Center of Biomedical Research Excellence (COBRE). Dr. Sedivy is the Director of the Center; other than a fraction of his salary, this award does not fund projects in his laboratory.
Role: PI/Director

COMPLETED RESEARCH SUPPORT

2 P20 RR15578-05, Sedivy, JM (PI) 10/01/2000-6/30/2005
NIH/NCRR
Center for Genetics and Genomics
This award funded several interdiciplinary projects and core facilities in a Center of Biomedical Research Excellence (COBRE). Dr. Sedivy was the Director of the Center; other than a fraction of his salary, this award did not fund projects in his laboratory.
Role: PI/Director

PENDING RESEARCH SUPPORT

None

Selected Publications

• Herbig, U. and Sedivy, J.M. (2006). Regulation of growth arrest in senescence: telomere damage is not the end of the story. Mech. Ageing Dev. 127: 16-24.(2006)
• Herbig, U., Ferreira, M., Condel, L., Carey, D. and Sedivy, J.M. (2006). Cellular Senescence in Aging Primates. Science 10.1126. Refer to weblinks to see reprint and abstract(2006)
• Guney, I., Wu, S. and Sedivy, J.M. (2006). Reduced c-Myc signaling triggers telomere-independent senescence by regulating the polycomb repressor Bmi-1 and the CDK inhibitor p16INK4a. Proc. Natl. Acad. Sci. USA, in press.(2006)
• Herbig, U., Ferreira, M., Condel, L., Carey, D. and Sedivy, J.M.(2006) Cellular Senescence in Aging Primates. Science 10.1126. Reffer to weblinks to see the abstract and the reprint(2006)
• Herbig, U. and Sedivy, J.M. (2005). regulation of growth arrets in senescence: telomere damage is not the end of the story. Mech. Ageing Dev. in press.(2005)
• Tamura, K., Hua, B., Adachi, S., Guney, I., Kawauchi, J., Morioka, M., Tamamori-Adachi, M., Tanaka, Y., Nakabeppu, Y., Sunamori, M., Sedivy, J.M. and Katajima, S. (2005). Stress response gene ATF3 is a target of c-myc in serum-induced cell proliferation. EMBO J. 24:2590-2601.(2005)
• Munoz-Alonso, M.J., Acosta, J.C., Richard, C., Delgado, M.D., Sedivy, J.M. and Leon, J. (2005). p21 Cip1 and p27 Kip1 induce distinct cell cycle effects and differentiation programs in myeloid leukemia cells. J. Biol. Chem. 280: 18120-18129.(2005)
• Rothermund, K., Rogulski, K., Fernandes, E., Whiting, A., Sedivy, J.M., Pu, L. and Prochownik, E.V. (2005). c-Myc-independent restoration of multiple phenotypes by two c-Myc target genes with overlapping functions. Cancer Res. 65: 2097-2107.(2005)
• Remondini, D., O'Connell, B., Intrator, N., Sedivy, J.M., Neretti, N., Castellani, G.C. and Cooper, L.N. (2005). Targeting c-Myc activated genes via a correlation method: detection of global changes in large gene expression network dynamics. Proc. Natl. Acad. Sci. USA 102: 6902-6906.(2005)
• Kujoth, G.C., Hiona, A., Pugh, T.D., Someya, S., Panzer, K., Wohlgemuth, S., Hofer, T., Hacker, T.A., Seo, A.Y., Sullivan, R., Jobling, W.A., Morrow, J., Van Remmen, H., Sedivy, J.M., Yamasoba, T., Tanokura, M., Saupe, K.W., Weindruch, R., Leeuwenburgh C. and Prolla, T.A. (2005). Mitochondrial DNA mutations, oxidative stress and apoptosis in mammalian aging. Science 309: 481-484.(2005)
• Sheffler, W., Upfal, E., Sedivy, J.M. and Noble, W.S. (2005). A learned comparative expression measure for Affymetrix GeneChip DNA microarrays. Proceedings of the 2005 IEEE Computational Systems Bioinformatics Conference, Stanford, CA: pp. 144-154.(2005)
• Charrier-Savourin, F.B., Chateau, M.T., Gire, V., Sedivy, J.M., Piette, J. and Dulic, V. (2004). p21-mediated nuclear retention of cyclin B1-Cdk1 in response to genotoxic stress. Mol. Biol. Cell 15: 3965-3976.(2004)
• Herbig, U., Jobling, W.A., Chen, B.P.C., Chen, D.J. and Sedivy, J.M. (2004). Telomere shortening triggers replicative senescence of human cells through a signaling pathway involving ATM, p53 and p21CIP1 but not p16INK4a. Mol. Cell 14: 501-513.(2004)
• Martin-Ruiz, C., Saretzki, G., Petrie, J., Ladhoff, J., Jeyapalan, J., Wei, W., Sedivy, J.M. and von Zglinicki, T. (2004). Stochastic variation in telomere shortening rate causes heterogeneity of human fibroblast replicative lifespan. J. Biol. Chem. 279: 17826-17833.(2004)
• Hindley, A.D., Park, S., Wang, L., Shah, K., Wang, Y., Hu, X., Shokat, K.M., Kolch, W., Sedivy, J.M. and Yeung, K.C. (2004). Engineering the serine/threonine protein kinase Raf-1 to utilize an orthogonal analogue of ATP substituted at the N6 position. FEBS Lett. 556: 26-34.(2004)
• Chatterjee, D., Bai, Y., Wang, Z., Beach, S., Mott, S., Roy, R., Braastad, C., Sun, Y., Mukhopadhyay, A., Aggarwal, B.B., Darnowski, J., Pantazis, P., Wyche, J., Fu, Z., Kitagwa, Y., Keller, E.T., Sedivy, J.M. and Yeung, K.C. (2004). RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis. J. Biol. Chem. 279: 17515-17523.(2004)
• Csoka, A.B., English, S.B., Simkevich, C.P., Ginzinger, D.G., Butte, A.J., Schatten, G.P., Rothman, F.G. and Sedivy, J.M. (2004). Genome-scale expression profiling of Hutchinson-Gilford Progeria Syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis. Aging Cell 3: 235-243.(2004)
• Smith, K.P., Byron, M., O'Connell, B., Tam, R., Schorl, C., Guney, I., Hall, L.L., Agrawal, P., Sedivy, J.M. and Lawrence, J.B. (2004). c-Myc localization within the nucleus: evidence for association with the PML nuclear body. J. Cell. Biochem. 93: 1282-1296.(2004)
• Wei, W., Herbig, U., Wei, S., Dutriaux, A. and Sedivy, J.M. (2003). Loss of Rb but not p16 function allows bypass of replicative senescence in human fibroblasts. EMBO R. 4: 1061-1066.(2003)
• Ma, W., Hommel, C., Brenneisen, P., Peters, T., Smit, N., Sedivy, J.M., Scharffetter-Kochanek, K. and Wlaschek, M. (2003). Long-term growth arrest of PUVA-treated fibroblasts in G2/M in the absence of p16INK4a, p21CIP1 or p53. Exp. Dermatol. 12: 629-637.(2003)
• Sedivy, J.M. (2003). Reproductive cloning conserves cellular senescence (invited News & Views article). Nat. Cell Biol. 5: 495-496.(2003)
• Junqueira, D., Cilenti, L., Musumeci, L., Sedivy, J.M. and Zervos, A.S. (2003). Random mutagenesis of the PDZOmi domain and selection of mutants that specifically bind the Myc protooncogene and induce apoptosis. Oncogene 22: 2772-2781.(2003)
• Hemmer, R.M., Wei, W., Dutriaux, A. and Sedivy, J.M. (2003). Somatic cell knockouts of tumor suppressor genes. In: Methods in Molecular Biology, vol. 223, Tumor Suppressor Genes. Wafik S. El-Deiry, Editor. Humana Press, Totowa, New Jersey, USA. pp. 187-206.(2003)
• Wei, W., Jobling, W.A., Chen, W., Hahn, W.C. and Sedivy, J.M. (2003). Abolition of cyclin-dependent kinase inhibitors p16Ink4a and p21Cip1/Waf1 functions permits Ras-induced anchorage-independent growth in telomerase-immortalized human fibroblasts. Mol. Cell. Biol. 23: 2859-2870.(2003)
• Schorl, C. and Sedivy, J.M. (2003). Loss of protooncogene c-Myc function impedes G1 phase progression both before and after the restriction point. Mol. Biol. Cell. 14: 823-835.(2003)
• O'Connell, B.C., Cheung, A.F., Simkevich, C.P., Tam, W., Ren, X., Mateyak, M.K. and Sedivy, J.M. (2003). A large scale genetic analysis of c-Myc-regulated gene expression patterns. J. Biol. Chem. 278: 12563-12573.(2003)
• Sedivy, J.M., Shippen, D.E. and Shakirov, E.V. (2003). Surprise ending (invited News & Views article). Nat. Genet. 33: 114-116.(2003)
• Collins, C.J. and Sedivy, J.M. (2003). Involvement of the INK4a/ARF gene locus in senescence. Aging Cell 2: 145-150..(2003)
• Lindvall, C., Hou, M., Komurasaki, T., Zheng, C., Henriksson, M., Sedivy, J.M., Bjorkholm, M., Teh, B.T., Nordenskjold, M. and Xu, D. (2003). Molecular characterization of human telomerase reverse transcriptase-immortalized human fibroblasts by expression profiling: activation of the Epiregulin gene. Cancer Res. 63: 1743-1747.(2003)
• Herbig, U., Wei, W., Dutriaux, A., Jobling, W.A. and Sedivy, J.M. (2003). Real time imaging of transcriptional activation in live cells reveals rapid upregulation of the cyclin-dependent kinase inhibitor gene CDKN1A in replicative cellular senescence. Aging Cell 2:295-304.(2003)
• You, Z., Madrid, L.V., Saims, D., Sedivy, J.M. and Wang, C.Y. (2002). c-Myc sensitizes cells to tumor necrosis factor-mediated apoptosis by inhibiting nuclear factor _B transactivation. J. Biol. Chem. 277: 36671-36677.(2002)
• Nikiforov, M.A., Chandriani, S., O'Connell, B., Petrenko, O., Kotenko, I., Beavis, A., Sedivy, J.M. and Cole, M.D. (2002). A functional screen for Myc-responsive genes reveals serinehydroxymethyltransferase, a major source of the one-carbon unit for cell metabolism. Mol. Cell. Biol. 22: 5793-5800.(2002)
• Obaya, A.J., Kotenko, I., Cole, M.D. and Sedivy, J.M. (2002). The protooncogene c-Myc acts through the cyclin-dependent kinase inhibitor p27Kip1 to facilitate the activation of cyclin-dependent kinase 4/6 and early G1 phase progression. J. Biol. Chem. 277: 31263-31269.(2002)
• Han, Z., Wei, W., Dunaway, S., Darnowski, J.W., Calabresi, P., Sedivy, J.M., Hendrickson, E.A., Balan, K., Pantazis, P. and Wyche, J.H. (2002). Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin. J. Biol. Chem. 277: 17154-17160.(2002)
• Sedivy, J.M. (2002). Gene targeting comes to top-down drug screens. Trends Biotechnol. 20: 92-93.(2002)
• Obaya, A.J. and Sedivy, J.M. (2002). Regulation of Cyclin-Cdk Activity in Mammalian Cells. Cell. Mol. Life Sci. 59: 126-142.(2002)
• Raderschall, E., Bazarov, A., Cao, J., Lurz, R., Smith, A., Mann, W., Ropers, H.-H., Sedivy, J.M., Golub, E.I., Fritz, E. and Haaf, T. (2002). Formation of nuclear Rad51 structures is functionally linked to p21 expression and protection from DNA-damage-induced apoptosis. J. Cell Sci. 115: 153-164.(2002)
• Bunz, F., Fauth, C., Speicher, M.R., Dutriaux, A., Sedivy, J.M., Kinzler, K.W., Vogelstein, B. ans Lengauer, C. (2002). Targeted inactivation of p53 in human cells does not result in aneuploidy. Cancer Res. 62: 1129-1133.(2002)
• Wang, Z., Bhattacharya, N., Mixter, P.F., Wei, W., Sedivy, J.M. and Magnuson, N.S. (2002). Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase. Biochim. Biophys. Acta 1593: 45-55.(2002)
• Sedivy, J.M. (2001). The cellular immortalization process: relevant issues for the generation of cell substrates for production of vaccines and other biologicals. In: F. Brown, A.M. Lewis, K. Peden and P. Krause (eds.), Evolving Sientific and Regulatory Perspectives on Cell Substrates for Vaccine Development. Dev. Biol. (Basel) 106: 479-488.(2001)
• Yeung, K.C., Rose, D.W., Dhillon, A.S., Yaros, D., Gustafsson, M., Chatterjee, D., McFerran, B., Wyche, J., Kolch, W. and Sedivy, J.M. (2001). Raf kinase inhibitor protein interacts with NF-_B-inducing kinase and TAK1 and inhibits NF-kB activation. Mol Cell. Biol. 21: 7207-7217.(2001)
• Adachi, S., Obaya, A.J., Han, Z., Ramos-Desimone, N., Wyche, J.H. and Sedivy, J.M. (2001). c-Myc is necessary for DNA damage-induced apoptosis in the G2 phase of the cell cycle. Mol. Cell. Biol. 21: 4929-4937.(2001)
• Bowman, T., Broome, M.A., Sinibaldi, D., Wharton, W., Pledger, W.J., Sedivy, J.M. Irby, R., Yeatman, T., Courtneidge, S.A. and Jove, R. (2001). Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc. Natl. Acad. Sci. USA 98: 7319-7324.(2001)
• Bazarov, A.V., Adachi, S., Li, S., Mateyak, M.K., Wei, S. and Sedivy, J.M. (2001). A modest reduction in c-Myc expression has minimal effects on cell growth and apoptosis but dramatically reduces susceptibility to Ras and Raf transformation. Cancer Res. 61: 1178-1186.(2001)
• Soucie, E.L., Annis, M.G., Sedivy, J.M., Filmus, J., Leber, B., Andrews, D.W. and Penn, L.Z. (2001), Myc potentiates apoptosis by stimulating Bax activity at the mitochondria. Mol. Cell. Biol. 21: 4725-4736.(2001)
• Wei, W., Hemmer, R.M. and Sedivy, J.M. (2001). The role of p14ARF in replicative and induced senescence of human fibroblasts. Mol. Cell. Biol. 21: 6748-6757.(2001)
• Landay, M., Oster, S.K., Khosravi, F., Grove, L.E., Yin, X., Sedivy, J.M., Penn, L.Z. and Prochownik, E.V. (2000). Promotion of growth and apoptosis in c-myc nullizygous fibroblasts by other members of the myc oncoprotein family. Cell Death Differ. 7: 697-705.(2000)
• Oster, S.K., Marhin, W.W., Asker, C., Facchini, L.M., Bion, P.A., Funa, K., Post, M., Sedivy, J.M. and Penn, L.Z. (2000). Myc is an essential negative regulator of platelet-derived growth factor beta receptor expression. Mol. Cell. Biol. 20: 6768-6778.(2000)
• Hermeking, H., Rago, C., Schuhmacher, M., Li, Q., Barrett, J.F., Obaya, A.J., O'Connell, B.C., Mateyak, M.K., Tam, W., Kohlhuber, F., Dang, C.V., Sedivy, J.M., Eick, D., Vogelstein, B. and Kinzler, K.W. (2000). Identification of CDK4 as a target of c-MYC. Proc. Natl. Acad. Sci. U. S. A. 97: 2229-2234.(2000)
• Yeung, K.C, Janosch, P., McFerran, B., Rose, D.W., Mischak, H., Sedivy, J.M. and Kolch, W. (2000). The mechanism of suppression of the Raf/MEK/ERK pathway by the RKIP inhibitor protein. Mol. Cell. Biol. 20: 3079-3085.(2000)
• Chuang, Y.Y.E., Chen, Q., Brown, J.P., Sedivy, J.M. and Liber, H.L. (1999). Radiation-induced mutations at the autosomal thymidine kinase locus are not elevated in p53-null cells. Cancer Res. 59: 3073-3076. Published correction appears in Cancer Res. 59: 5400.(1999)
• Wei, W. and Sedivy, J.M. (1999). Differentiation between senescence (M1) and crisis (M2) in human fibroblast cultures. Exp. Cell Res. 253: 519-522.(1999)
• Mateyak, M.K., Obaya, A.J. and Sedivy, J.M. (1999). c-Myc regulates cyclin D/Cdk4/6 activity but affects cell cycle progression at multiple independent steps. Mol. Cell. Biol. 19: 4672-4683.(1999)
• Obaya, A.J., Mateyak, M.K. and Sedivy, J.M. (1999). Mysterious liaisons: the relationship between c-Myc and the cell cycle. Oncogene 18: 2934-2941.(1999)
• Wei, S., Wei, W. and Sedivy, J.M. (1999). Expression of catalytically active telomerase does not prevent premature senescence caused by overexpression of oncogenic Ha-Ras in normal human fibroblasts. Cancer Res. 59: 1539-1543.(1999)
• Sedivy, J.M., Vogelstein, B., Liber, H.L., Hendrickson, E. and Rosmarin, A. (1999). Gene targeting in human cells without isogenic DNA. Science 283: 9-9a.(1999)
• Sedivy, J.M. and Dutriaux, A. (1999). Gene targeting and somatic cell genetics: a rebirth or a coming of age? Trends Genet. 14: 88-90.(1999)
• Yeung, K.C., Seitz, T., Li, S., Janosch, P., McFerran, B., Kaiser, C., Fee, F., Katsanakis, K.D., Rose, D.W., Mischak, H., Sedivy, J.M. and Kolch, W. (1999). Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 401: 173-177.(1999)
• Xiao, Q., Claassen, G., Shi, J., Adachi, S., Sedivy, J.M. and Hann, S.R. (1998). Transactivation-defective c-MycS retains the ability to regulate growth and apoptosis. Genes Dev. 12: 3803-3808.(1998)
• Bush, A., Mateyak, M.K., Dugan, K., Obaya, A., Adachi, S., Sedivy, J.M. and Cole, M.D. (1998). c-myc null cells misregulate cad and gadd45 but not other proposed c-Myc targets. Genes Dev. 12: 3797-3802.(1998)
• Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J.P., Sedivy, J.M., Kinzler, K.W. and Vogelstein, B. (1998). The induction of p21 by p53 is required for sustained G2 arrest following DNA damage. Science 282: 1497-1501.(1998)
• Sedivy, J.M. (1998). Can ends justify the means?: Telomeres and the mechanisms of replicative senescence and immortalization in mammalian cells. Proc. Natl. Acad. Sci. USA, 95: 9078-9081.(1998)
• Lu, K.K., Bazarov, A.V., Yoon, L.S. and Sedivy, J.M. (1998). Isolation of temperature-sensitive mutations in the c-raf-1 catalytic domain and expression of conditionally active and dominant-defective forms of Raf-1 in cultured mammalian cells. Cell Growth Diff., 9: 367-380.(1998)
• Prouty, S.M., Maroo, A., Maucher, C., Mischak, H., Kolch, W. and Sedivy, J.M. (1998). Studies of perinuclear and nuclear translocation of the Raf-1 protein in rodent fibroblasts. Biochim. Biophys. Acta, 1404: 6-16.(1998)
• Counter, C.M., Hahn, W.C., Wei, W., Dickinson-Caddle, S., Beijersbergen, R.L., Lansdorp, P.M., Sedivy, J.M. and Weinberg, R.A. (1998). Dissociation between in vitro telomerase activity, telomere maintenance and cellular immortalization. Proc. Natl. Acad. Sci. USA 95: 14723-14728.(1998)
• Shichiri, M., Adachi, S., Sedivy, J.M. and Marumo, F. (1997). Biphasic regulation of the preproendothelin-1 gene by c-myc. Endocrinology 138: 4584-4590.(1997)
• Mateyak, M.K., Obaya, A.J., Adachi, S. and Sedivy, J.M. (1997). Phenotypes of c-Myc-deficient fibroblasts isolated by targeted homologous recombination. Cell. Growth Diff. 8: 1039-1048.(1997)
• Brown, J.P., Wei, W. and Sedivy, J.M. (1997). Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277: 831-834.(1997)
• Weissinger, E.M., Eissner, G., Grammer, C., Fackler, S., Haefner, B., Yoon, L.S., Lu, K.L., Bazarov, A., Sedivy, J.M., Mischak, H. and Kolch, W. (1997). Inhibition of the Raf-1 kinase by cAMP agonists causes apoptosis of v-abl transformed cells. Mol. Cell. Biol. 17: 3229-3241.(1997)
• Shichiri, M., Sedivy, J.M., Marumo, F. and Hirata, Y. (1997). Endothelin-1 is a potent survival factor for c-Myc-dependent apoptosis. Mol. Endocrinol., 12: 172-180.(1997)
• Janosch, P., Schellerer, M., Seitz, T., Reim, P., Eulitz, M., Brielmeier, M., Kolch, W., Sedivy, J.M. and Mischak, H. (1996). Characterization of IkB kinases: IkB-_ is not phosphorylated by Raf-1 or protein kinase C isozymes, but is a casein kinase II substrate. J. Biol. Chem. 271: 13868-13874.(1996)
• Yang, T.-A., Heiser, W.C. and Sedivy, J.M. (1995). Efficient in situ electroporation of mammalian cells grown on microporous membranes. Nucleic Acids Res. 23: 2803-2810.(1995)
• Brown, J.P. and Sedivy, J.M. (1995). What could be simpler? Using human cells to study human cancer. J. Am. Anti-Vivisect. Soc. 103: 15-18.(1995)
• Li, S., Janosch, P., Tanji, M., Rosenfeld, G.C., Waymire, J.C., Mischak, H., Kolch, W. and Sedivy, J.M. (1995). Regulation of Raf-1 kinase activity by the 14-3-3 family of proteins. EMBO J., 14: 685-696.(1995)
• Hanson, K.D., and Sedivy, J.M. (1995). Analysis of biological selections for high efficiency gene targeting. Mol. Cell. Biol. 15: 45-51.(1995)
• Hanson, K.D., Shichiri, M., Follansbee, M.R. and Sedivy, J.M. (1994). Effects of c-myc expression on cell cycle progression. Mol. Cell. Biol. 14: 5748-5755.(1994)
• Karantza, V., Maroo, A., Fay, D. and Sedivy, J.M. (1993). Overproduction of Rb protein after the G1/S boundary causes G2 arrest. Mol. Cell. Biol. 13: 6640-6652.(1993)
• Li, S. and Sedivy, J.M. (1993). Raf-1 protein kinase activates the NF-_B transcription factor by dissociating the cytoplasmic NF-_B/I_B complex. Proc. Natl. Acad. Sci. USA 90: 9247-9251.(1993)
• Shichiri, M., Hanson, K.D. and Sedivy, J.M. (1993). The effects of c-myc expression on proliferation, quiescence, and the G0 to G1 transition in nontransformed cells. Cell Growth Diff. 4: 93-104.(1993)
• Prouty, S.M., Hanson, K.D., Boyle, A.L., Brown, J.R., Shichiri, M., Follansbee, M.R., Kang, W. and Sedivy, J.M. (1993). A cell culture model system for genetic analyses of the cell cycle by targeted homologous recombination. Oncogene 8: 899-907.(1993)
• 13. Sedivy, J.M. and Joyner, A. (1992). Gene Targeting. W.H. Freeman Press, NY.(1992)
• Sedivy, J.M. (1991). Pilot scale protein production using inducible gene amplification. In: Animal Cell Culture and Production of Biologicals, R. Sasaki and K. Ikura (eds.), Kluwer Academic Publishers, Dordrecht, Netherlands, pp. 251-258.(1991)
• Young, J.I., Sedivy, J.M. and Smith, J.R. (2003). Telomerase expression in normal human fibroblasts stabilizes DNA 5-methycytosine transferase I (DNMT1). J. Biol. Chem. 278: 19904-19908.(1990)
• Leonardo, E.D. and Sedivy, J.M. (1990). A new vector for cloning large eukaryotic DNA segments in E. coli. Bio/Technology 8: 841-844.(1990)
• Schnipper, L.E., Chan, V., Sedivy, J.M., Jat, P.S. and Sharp, P.A. (1989). Gene activation by induced DNA rearrangements. Cancer Res. 49: 6640-6644.(1989)
• Sedivy, J.M. and Sharp, P.A. (1989). Positive genetic selection for gene disruption in mammalian cells by homologous recombination. Proc. Natl. Acad. Sci. USA 86: 227-231.(1989)
• Sedivy, J.M. (1988). New genetic methods for mammalian cells. Bio/Technology, 6: 1192-1196.(1988)
• Sedivy, J.M., Capone, J.P., RajBhandary, U.L. and Sharp, P.A. (1987). An inducible mammalian amber suppressor: propagation of a poliovirus mutant. Cell 50: 379-389.(1987)
• Capone, J.P., Sedivy, J.M., Sharp, P.A. and RajBhandary, U.L. (1986). Introduction of UAG, UAA and UGA nonsense mutations at a specific site in the Escherichia coli chloramphenicol acetyltransferase gene: use in measurement of amber, ochre and opal suppression in mammalian cells. Mol. Cell. Biol. 6: 3059-3067.(1986)
• Sedivy, J.M., Babul, J. and Fraenkel, D.G. (1986). AMP-insensitive fructose bisphosphatase in Escherichia coli and its consequences. Proc. Natl. Acad. Sci. USA 83: 1656-1659.(1986)
• Sedivy, J.M. and Fraenkel, D.G. (1985). Fructose bisphosphatase of Saccharomyces cerevisiae: cloning, disruption and regulation of the FBP1 gene. J. Mol. Biol. 186: 307-319.(1985)
• Sedivy, J.M., Daldal, F. and Fraenkel, D.G. (1984). Fructose bisphosphatase of Escherichia coli: Cloning of the structural gene (fbp) and preparation of a chromosomal deletion. J. Bacteriol. 158: 1048-1053.(1984)
• Geisselsoder, J., Sedivy, J.M., Walsh, R.B. and Goldstein, R. (1982). Capsid structure of satellite phage P4 and its P2 helper. J. Ultrastruct. Res. 79: 165-173.(1982)
• Goldstein, R., Sedivy, J.M. and Ljungquist, E. (1982). Propagation of satellite phage P4 as a plasmid. Proc. Natl. Acad. Sci. USA 79: 515-519.(1982)