Research Topics
Genomes and GenesSpecies | NORMAN SHARPLESSSummaryAffiliation: University of North Carolina Country: USA Publications
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Publications
Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapyPatrick J Roberts
Department of Genetics, The University of North Carolina School of Medicine, Chapel Hill, NC, USA
J Natl Cancer Inst 104:476-87. 2012....- Telomeres, stem cells, senescence, and cancerNorman E Sharpless
Department of Medicine and Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 8212, USA
J Clin Invest 113:160-8. 2004..g., p16(INK4a)-Rb, ARF-p53, and the telomere) have evolved to ward against this possibility. These beneficial antitumor pathways, however, appear also to limit the stem cell life span, thereby contributing to aging... 
The differential impact of p16(INK4a) or p19(ARF) deficiency on cell growth and tumorigenesisNorman E Sharpless
Department of Medicine, Lineberger Cancer Center, CB 7295, The University of North Carolina School of Medicine, Chapel Hill, NC 27599 7295, USA
Oncogene 23:379-85. 2004....- Ink4a/Arf links senescence and agingNorman E Sharpless
Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC 27599 7295, USA
Exp Gerontol 39:1751-9. 2004..Expression of the INK4a/ARF locus, therefore, appears not only to be a major suppressor of cancer, but also an effector of mammalian aging... - INK4a/ARF: a multifunctional tumor suppressor locusNorman E Sharpless
Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, 27599 7295, USA
Mutat Res 576:22-38. 2005.... - The mighty mouse: genetically engineered mouse models in cancer drug developmentNorman E Sharpless
Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599 7295, USA
Nat Rev Drug Discov 5:741-54. 2006.... - How stem cells age and why this makes us grow oldNorman E Sharpless
Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599 7295, USA
Nat Rev Mol Cell Biol 8:703-13. 2007.... 
HMGA2, microRNAs, and stem cell agingScott M Hammond
Department of Cell and Developmental Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Cell 135:1013-6. 2008..2008; Nishino et al., 2008; Sanna et al., 2008; Weedon et al., 2008) link a chromatin-associated protein, HMGA2, to development, height, and mouse stem cell aging during late fetal development and young adulthood...- CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality controlJin Na Min
Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina 27599 7126, USA
Mol Cell Biol 28:4018-25. 2008..Taken together, these data reveal that impaired protein quality control contributes to cellular senescence and implicates CHIP-dependent quality control mechanisms in the regulation of mammalian longevity in vivo... - Expression of p16Ink4a compensates for p18Ink4c loss in cyclin-dependent kinase 4/6-dependent tumors and tissuesMatthew R Ramsey
Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 7295, USA
Cancer Res 67:4732-41. 2007..These data suggest that p16(Ink4a) and p18(Ink4c) coordinately regulate the in vivo catalytic activity of cdk4/6 in specific compartments of adult mice... - Defective cell cycle checkpoint functions in melanoma are associated with altered patterns of gene expressionWilliam K Kaufmann
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
J Invest Dermatol 128:175-87. 2008..The results suggest that defects in DNA damage checkpoints may be recognized in melanomas through analysis of gene expression... - HIF2alpha cooperates with RAS to promote lung tumorigenesis in miceWilliam Y Kim
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA
J Clin Invest 119:2160-70. 2009..They further suggest a possible causal relationship between HIF2alpha and prognosis in patients with NSCLC... - Overexpression of the cell cycle inhibitor p16INK4a promotes a prothrombotic phenotype following vascular injury in miceJessica C Cardenas
Department of Pathology and Laboratory Medicine, University of North Carolina Chapel Hill, NC 27599 7035, USA
Arterioscler Thromb Vasc Biol 31:827-33. 2011..p16(INK4a) is a cell cycle inhibitor that promotes senescence and is upregulated during normal aging. In this study, we examine the contribution of p16(INK4a) overexpression to venous thrombosis... - The persistence of senescenceNorman E Sharpless
Department of Medicine, Lineberger Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Sci Aging Knowledge Environ 2003:PE24. 2003..In this Perspective, I discuss two recent publications (1, 2) that deal with the durability of senescence. These findings are of interest not only to those who study aging, but to those who study cancer as well... - Hot topics in stem cells and self-renewal: 2010Norman E Sharpless
Department of Medicine and Genetics, The University of North Carolina School of Medicine, Chapel Hill, NC 27599 7295, USA
Aging Cell 9:457-61. 2010..This period has also been marked by the recent award of the Nobel Prize in Physiology or Medicine for elucidation of telomeres and telomerase, a topic of critical importance to stem cell aging... - Lack of extracellular signal-regulated kinase mitogen-activated protein kinase signaling shows a new type of melanomaJaniel M Shields
Department of Biochemistry and Biophysics, The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Cancer Res 67:1502-12. 2007..These results show a molecularly distinct melanoma subtype that does not require ERK activation or epithelial-mesenchymal transformation for progression... - p53: good cop/bad copNorman E Sharpless
Department of Adult Oncology, Dana-Farber Cancer Institute, Department of Medicine and Genetics, Harvard Medical School, Boston, MA 02115, USA
Cell 110:9-12. 2002..By extension, this relationship implies that therapies aimed to reduce cancer and postpone aging, and thereby increase longevity, will necessarily work either upstream or downstream, but not on the level of, p53... - LKB1 and lung cancer: more than the usual suspectsUsman Shah
Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
Cancer Res 68:3562-5. 2008..One is reminded of an Agatha Christie murder mystery where nearly every character in the book has reason to be suspected of committing the crime-there are too many suspects for how LKB1 might repress lung cancer... - Stem cells and the rate of livingJanakiraman Krishnamurthy
Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Cell Stem Cell 1:9-11. 2007..While this theory as originally conceived has been debunked, new work (Ruzankina et al. [2007], in this issue of Cell Stem Cell) suggests that mammals in fact do have a finite number of stem cell replications per life... - The regulation of INK4/ARF in cancer and agingWilliam Y Kim
Department of Medicine, The University of North Carolina School of Medicine, Chapel Hill, 27599, USA
Cell 127:265-75. 2006..Here, we discuss the regulation and role of p16(INK4a), ARF, and p15(INK4b) in cancer and aging... - p16(Ink4a) inhibits histologic progression and angiogenic signaling in min colon tumorsSteven L Gibson
Department of Medicine, Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6140, USA
Cancer Biol Ther 4:1389-94. 2005..01). Exogenous p16 expression in human colon tumor cells in vitro inhibited VEGF production. These results suggest that p16 constrains colon tumor progression, in part through inhibiting angiogenic signaling... - p16INK4a induces an age-dependent decline in islet regenerative potentialJanakiraman Krishnamurthy
Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
Nature 443:453-7. 2006..These genetic data support the view that an age-induced increase of p16INK4a expression limits the regenerative capacity of beta-cells with ageing... - Tumor suppressor mechanisms in immune agingYan Liu
Department of Genetics and Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Curr Opin Immunol 21:431-9. 2009..Here we will argue on the basis of recent advances in our understanding of tumor suppressor mechanisms in immune cells; however, that aspects of these same beneficial pathways have the potential to induce intrinsic immune aging... - RNA expression analysis of formalin-fixed paraffin-embedded tumorsShannon K Penland
Department of Medicine, The University of North Carolina School of Medicine, Chapel Hill, NC 27599 7295, USA
Lab Invest 87:383-91. 2007..Although only a minority of FFPE blocks could be analyzed, we show that informative RNA expression analysis can be derived from selected FFPE samples... - CD200 is induced by ERK and is a potential therapeutic target in melanomaKimberly B Petermann
Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 7295, USA
J Clin Invest 117:3922-9. 2007.... - Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibitionSøren M Johnson
Department of Genetics, The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
J Clin Invest 120:2528-36. 2010..These results demonstrate an effective method to mitigate the hematopoietic toxicity of IR in mammals, which may be potentially useful after radiological disaster or as an adjuvant to anticancer therapy... - What's so special about RB?Christin E Burd
Department of Genetics, The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599 7295, USA
Cancer Cell 17:313-4. 2010..However, only RB is frequently mutated in cancer. In this issue of Cancer Cell, Chicas et al. shed new light on this conundrum, defining a "special," nonredundant role for RB in promoting cellular senescence... - Ink4a/Arf expression is a biomarker of agingJanakiraman Krishnamurthy
Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599 7295, USA
J Clin Invest 114:1299-307. 2004..These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging... - A quantitative model for age-dependent expression of the p16INK4a tumor suppressorDenis Tsygankov
Departments of Pharmacology, Medicine, and Genetics, and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Proc Natl Acad Sci U S A 106:16562-7. 2009..This analysis is most consistent with the model that p16(INK4a) expression monotonically increases with age, and higher expression is associated with increased subject attrition... - Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human agingYan Liu
Department of Genetics, The University of North Carolina School of Medicine, Chapel Hill, USA
Aging Cell 8:439-48. 2009..These data suggest that p16(INK4a) expression in PBTL is an easily measured, peripheral blood biomarker of molecular age... - INK4/ARF transcript expression is associated with chromosome 9p21 variants linked to atherosclerosisYan Liu
Department of Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, USA
PLoS ONE 4:e5027. 2009..To explore the mechanism of this association, we investigated whether expression of proximate transcripts (p16(INK4a), p15(INK4b), ARF, ANRIL and MTAP) correlate with genotype of representative 9p21 SNPs... - RAS unplugged: negative feedback and oncogene-induced senescenceNabeel Bardeesy
Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA
Cancer Cell 10:451-3. 2006.... - Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticlesWuping Li
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 7352, USA
Mol Ther 16:1252-60. 2008..Application of this technology to alternative cell/tissue types using AAV or other viral capsid sequences is likely to yield a new class of biological nanoparticles as vectors for human gene transfer... - VHL inactivation: a new road to senescenceWilliam Y Kim
Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599 7295, USA
Cancer Cell 13:295-7. 2008.... - LKB1 modulates lung cancer differentiation and metastasisHongbin Ji
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
Nature 448:807-10. 2007..These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis... - Components of the Rb pathway are critical targets of UV mutagenesis in a murine melanoma modelKaruppiah Kannan
Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women s Hospital, Boston, MA 02115, USA
Proc Natl Acad Sci U S A 100:1221-5. 2003..Together, these molecular and genetic data identify components of the Rb pathway as critical biological targets of UV-induced mutagenesis in the development of murine melanoma in vivo... - p16(INK4a) and p53 deficiency cooperate in tumorigenesisNorman E Sharpless
Department of Adult Oncology, Dana Farber Cancer Institute and Harvard Medical School, 44 Binney Street M413, Boston, MA 02115, USA
Cancer Res 62:2761-5. 2002..This cooperation between p16(INK4a) and p53 loss in tumorigenesis is consistent with the view that these genes function in distinct anticancer pathways... - Constitutive telomerase expression promotes mammary carcinomas in aging miceSteven E Artandi
Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street M413, Boston, MA 02115, USA
Proc Natl Acad Sci U S A 99:8191-6. 2002..These data indicate that enforced mTERT expression can promote the development of spontaneous cancers even in the setting of ample telomere reserve... - Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformationNabeel Bardeesy
Department of Adult Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA
Nature 419:162-7. 2002..Together, our data rationalize several features of PJS polyposis--notably its peculiar histopathological presentation and limited malignant potential--and place Lkb1 in a distinct class of tumour suppressors... - A mouse model of human oral-esophageal cancerOliver G Opitz
Division of Gastroenterology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
J Clin Invest 110:761-9. 2002..These data demonstrate that L2D1(+)/p53(+/-) mice provide a well-defined, novel, and faithful model of oral-esophageal cancer, which allows for the testing of novel chemopreventive, diagnostic, and therapeutic approaches... - p16(Ink4a) interferes with Abelson virus transformation by enhancing apoptosisZohar Sachs
Department of Pathology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
J Virol 78:3304-11. 2004..These results indicate that both products of the Ink4a/Arf locus influence Ab-MLV transformation and reveal that in addition to its well-recognized effects on the cell cycle, p16(Ink4a) can suppress transformation by inducing apoptosis... - Impaired processing of DNA photoproducts and ultraviolet hypermutability with loss of p16INK4a or p19ARFPapri Sarkar-Agrawal
Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA
J Natl Cancer Inst 96:1790-3. 2004..These results may further explain why INK4a/ARF mutations predispose to malignant melanoma, a UV-induced tumor... - How disruption of cell cycle regulating genes might predispose to sun-induced skin cancerThomas M Rünger
Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA
Cell Cycle 4:643-5. 2005..Differences in the apoptotic response to ultraviolet light between melanocytes and keratinocytes might explain why INK4a/ARF mutations predispose to malignant melanoma, but not to keratinocyte-derived skin cancers... - Cancer: crime and punishmentNorman E Sharpless
Nature 436:636-7. 2005 - ARF functions as a melanoma tumor suppressor by inducing p53-independent senescenceLinan Ha
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892 4264, USA
Proc Natl Acad Sci U S A 104:10968-73. 2007..Thus, therapeutics designed to restore wild-type p53 function may be insufficient to counter melanoma and other malignancies in which ARF holds p53-independent tumor suppressor activity... - Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4aViktor Janzen
Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA
Nature 443:421-6. 2006..Inhibition of p16INK4a may ameliorate the physiological impact of ageing on stem cells and thereby improve injury repair in aged tissue... - Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageingAnna V Molofsky
Howard Hughes Medical Institute, Department of Internal Medicine, and Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan 48109 2216, USA
Nature 443:448-52. 2006..Declining subventricular zone progenitor function and olfactory bulb neurogenesis during ageing are thus caused partly by increasing p16INK4a expression... - Telomeres, p21 and the cancer-aging hypothesisJessica F Bell
Nat Genet 39:11-2. 2007 - ROS as a tumour suppressor?Matthew R Ramsey
Nat Cell Biol 8:1213-5. 2006 - Targeting of C-terminal binding protein (CtBP) by ARF results in p53-independent apoptosisSeema Paliwal
Department of Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA
Mol Cell Biol 26:2360-72. 2006..CtBP proteins represent putative targets for p53-independent tumor suppression by ARF... - Cancer biology: gone but not forgottenNorman E Sharpless
Nature 445:606-7. 2007 - Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axisRobert M Bachoo
Center for Neuro-Oncology, Boston, Massachusetts 02115, USA
Cancer Cell 1:269-77. 2002..These data support the view that dysregulation of specific genetic pathways, rather than cell-of-origin, dictates the emergence and phenotype of high-grade gliomas... - A phase II study of troglitazone, an activator of the PPARgamma receptor, in patients with chemotherapy-resistant metastatic colorectal cancerMatthew H Kulke
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
Cancer J 8:395-9. 2002..The median progression-free survival time was only 1.6 months, and the median survival time was 3.9 months. DISCUSSION: Troglitazone is not an active agent for the treatment of metastatic colorectal cancer... - Array comparative genome hybridization for tumor classification and gene discovery in mouse models of malignant melanomaRónán C O'Hagan
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
Cancer Res 63:5352-6. 2003..Kannan, et al., Proc. Natl. Acad. Sci. USA, 21: 2003). These results are the first to establish the utility of array-CGH as a means of etiology-based tumor classification in genetically defined cancer-prone models... - EGFR targeted therapy: view from biological standpointHongbin Ji
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
Cell Cycle 5:2072-6. 2006.... - The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapiesHongbin Ji
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
Cancer Cell 9:485-95. 2006..These data suggest that persistent EGFR signaling is required for tumor maintenance in human lung adenocarcinomas expressing EGFR mutants...
Research Grants
- Melanoma in p16INK4a and p19ARF Deficient MiceNORMAN SHARPLESS; Fiscal Year: 2006..Such a model could then serve as a foundation for future studies of melanoma progression and therapy, and the results of this work will have implications for the treatment of human MM. ..
- The role of p16INK4a in mammalian agingNORMAN SHARPLESS; Fiscal Year: 2007..Through these approaches, we will examine the in vivo tissue and age-specific effects of p16INK4a expression, and delineate its contribution to a variety of mammalian aging phenotypes. ..
- The role of p16INK4a in mammalian agingNorman Edward Sharpless; Fiscal Year: 2010..In this work, we use experimental systems in humans and mice to investigate the role of anti-cancer mechanisms in aging. ..