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Harriet Isom

TitleProfessor
InstitutionCollege of Medicine
DepartmentMicrobiology and Immunology
Address500 University Drive Hershey PA 17033
Mailbox: H107
Phone7175315877

 Overview 
 overview
PREFERRED TITLE/ROLE:

Distinguished Professor of Microbiology and Immunology, Professor of Pathology,

GRADUATE PROGRAM AFFILIATIONS:

Cell and Molecular Biology, MD/PhD Degree Program, Microbiology and Immunology

EDUCATION:

Ph.D., University of Illinois, 1973
Postdoctoral Training, University of Pennsylvania School of Medicine, 1973-1976

NARRATIVE:

The research in my laboratory focuses on utilizing in vitro cell culture systems to understand liver function and pathogenesis. The cell systems include primary rat hepatocytes in long-term dimethylsulfoxide (DMSO) culture, SV40 immortalized hepatocyte cell lines and cell lines of human hepatic origin. Our laboratory established an in vitro model in which hepatocytes are plated on collagen-coated plates and maintained in serum free medium supplemented with DMSO. These cells remain highly differentiated at a biochemical, molecular and morphological level for more than a year. Current studies can be divided into four related areas of research.

Regulation of Growth Control in Hepatocytes: A series of immortalized, transformed and tumor derived rat hepatocyte cell lines have been generated and characterized in our laboratory. The combination of hepatocytes in long-term DMSO culture and these hepatic cell lines can be used to examine progression to malignancy. We have previously determined that a1 integrin expression present in immortalized rat hepatocyte cell lines is lost when these cells are transformed by activated H-ras and short term expression of activated H-ras downregulates a1 integrin expression. The current aims are to determine whether a1 integrin expression plays a role in normal growth control in hepatocytes and how a1 integrin expression is regulated, in particular, by ras, in primary hepatocytes and hepatocyte cell lines. We have previously shown that TGFß1 treatment reverses the transformed phenotype of ras-transformed hepatic cell lines and also increases a1 integrin expression. The current aims are to elucidate the key players in the TGFß1 signaling pathway involved in suppressing the transformed phenotype, and/or inducing a1 integrin expression.

Apoptosis in Hepatocytes: We have recently shown that hepatocytes in long-term DMSO culture are an excellent model for studying apoptosis in hepatocytes. One advantage of this system over short term primary hepatocyte cultures is that the background level of spontaneous apoptosis is minimal. We have used this system to demonstrate that tumor necrosis factor a (TNFa can induce apoptosis in hepatocytes in long term culture, but only after the cells have been sensitized by removal of DMSO or treatment with cycloheximide. We have also demonstrated that hepatocytes in long-term DMSO culture can be used to study apoptosis induced by treatment with transforming growth factor ß or activation of Fas. The current aims are to dissect the cellular mechanisms that mediate TNFa-induced apoptosis in hepatocytes concentrating on identifying the proteins that interact with the TNF receptors and the aspects of the signaling pathway that are unique to hepatocytes. Recent technical advances that will facilitate our ability to achieve our goals are the development of a highly sensitive radioactive assay for oligonucleosomal DNA ladder formation and the use of baculoviruses to mediate gene delivery into primary hepatocytes. The latter will facilitate our ability to examine the effects of gain or loss of function of a specific gene on apoptosis.

Iron Metabolism and Metal-Induced Cellular Injury: Hemochromatosis is the term used to describe a state of iron overload in an individual. Eventually, after chronic iron overload, fibrosis occurs, the liver becomes cirrhotic and hepatocellular carcinomas may arise. Our goal is to use hepatocytes in culture to address the isolated issue of how iron-overload alters the function of well-differentiated hepatocytes in the absence of the other liver cell types. Recently, we have demonstrated that hepatocytes in long-term DMSO culture can be iron-loaded and can be used to study the effects of chronic iron loading on hepatocytes. Iron loading was accompanied by an increase in ferritin cores within lysosomes and an increase in total cellular ferritin. Our current aim is to test the hypothesis that iron loading of hepatocytes in long-term DMSO culture induces specific types of cellular damage which are potentiated if the cells are treated with cytokines. We will also characterize the molecular mechanism underlying ferritin induction caused by chronic iron overload.

Hepatitis B virus (HBV) Replication: We recently developed a novel transient mechanism for studying HBV gene expression and replication. Recombinant HBV baculovirus Autographa californica is used to deliver the HBV genome to human hepatoblast HepG2 cells. In HBV baculovirus infected HepG2 cells, HBV transcripts, intracellular and secreted HBV antigens are produced, enveloped HBV virions are secreted and replication occurs as evidenced by the presence of high levels of intracellular replicative intermediates and protected HBV DNA in the medium. Covalently closed circular (CCC) DNA is present indicating that, in this system, HBV core particles are capable of delivering newly synthesized HBV genomes back into the nuclei of infected cells. The recombinant HBV baculovirus system has numerous advantages over existing in vitro HBV expressing cell cultures systems. HBV CCC DNA can be rapidly detected from low numbers of HepG2 cells and the system lends itself readily to experimental manipulation. Our current aims are to use the system (1) to evaluate the effects of antivirals and/or cytokines on HBV replication, (2) to dissect specific aspects of HBV replication, and (3) to study the interaction of HBV with the host cell.


 Bibliographic 
 selected publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Moon MS, McDevitt EI, Zhu J, Stanley B, Krzeminski J, Amin S, Aliaga C, Miller TG, Isom HC. Elevated hepatic iron activates NF-E2-related factor 2-regulated pathway in a dietary iron overload mouse model. Toxicol Sci. 2012 Sep; 129(1):74-85.
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  2. Avella DM, Li G, Schell TD, Liu D, Zhang SS, Lou X, Berg A, Kimchi ET, Tagaram HR, Yang Q, Shereef S, Garcia LS, Kester M, Isom HC, Rountree CB, Staveley-O'Carroll KF. Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model. Hepatology. 2012 Jan; 55(1):141-52.
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  3. Moon MS, Kang BH, Krzeminski J, Amin S, Aliaga C, Zhu J, McDevitt EI, Kocher S, Richie JP, Isom HC. 3,5,5-trimethyl-hexanoyl-ferrocene diet protects mice from moderate transient acetaminophen-induced hepatotoxicity. Toxicol Sci. 2011 Dec; 124(2):348-58.
    View in: PubMed
  4. Tagaram HR, Divittore NA, Barth BM, Kaiser JM, Avella D, Kimchi ET, Jiang Y, Isom HC, Kester M, Staveley-O'Carroll KF. Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma. Gut. 2011 May; 60(5):695-701.
    View in: PubMed
  5. Moon MS, Richie JP, Isom HC. Iron potentiates acetaminophen-induced oxidative stress and mitochondrial dysfunction in cultured mouse hepatocytes. Toxicol Sci. 2010 Nov; 118(1):119-27.
    View in: PubMed
  6. Isom HC, McDevitt EI, Moon MS. Elevated hepatic iron: a confounding factor in chronic hepatitis C. Biochim Biophys Acta. 2009 Jul; 1790(7):650-62.
    View in: PubMed
  7. Heipertz RA, Starkey JL, Miller TG, Hu J, Isom HC. trans-Complementation of HBV rtM204I mutant replication by HBV wild-type polymerase. Virology. 2009 May 25; 388(1):57-67.
    View in: PubMed
  8. Starkey JL, Chiari EF, Isom HC. Hepatitis B virus (HBV)-specific short hairpin RNA is capable of reducing the formation of HBV covalently closed circular (CCC) DNA but has no effect on established CCC DNA in vitro. J Gen Virol. 2009 Jan; 90(Pt 1):115-26.
    View in: PubMed
  9. Shan W, Palkar PS, Murray IA, McDevitt EI, Kennett MJ, Kang BH, Isom HC, Perdew GH, Gonzalez FJ, Peters JM. Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) attenuates carbon tetrachloride hepatotoxicity by downregulating proinflammatory gene expression. Toxicol Sci. 2008 Oct; 105(2):418-28.
    View in: PubMed
  10. Heipertz RA, Miller TG, Kelley CM, Delaney WE, Locarnini SA, Isom HC. In vitro study of the effects of precore and lamivudine-resistant mutations on hepatitis B virus replication. J Virol. 2007 Apr; 81(7):3068-76.
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  11. Isom HC, Abdelhamed AM, Bilello JP, Miller TG. Baculovirus-mediated gene transfer for the study of hepatitis B virus. Methods Mol Med. 2004; 96:219-37.
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  12. Stoehr SA, Isom HC. Gap junction-mediated intercellular communication in a long-term primary mouse hepatocyte culture system. Hepatology. 2003 Nov; 38(5):1125-35.
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  13. Iocca HA, Isom HC. Tumor necrosis factor-alpha acts as a complete mitogen for primary rat hepatocytes. Am J Pathol. 2003 Aug; 163(2):465-76.
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  14. Bilello JP, Cable EE, Myers RL, Isom HC. Role of paracellular junction complexes in baculovirus-mediated gene transfer to nondividing rat hepatocytes. Gene Ther. 2003 May; 10(9):733-49.
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  15. Bilello JP, Cable EE, Isom HC. Expression of E-cadherin and other paracellular junction genes is decreased in iron-loaded hepatocytes. Am J Pathol. 2003 Apr; 162(4):1323-38.
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  16. Abdelhamed AM, Kelley CM, Miller TG, Furman PA, Cable EE, Isom HC. Comparison of anti-hepatitis B virus activities of lamivudine and clevudine by a quantitative assay. Antimicrob Agents Chemother. 2003 Jan; 47(1):324-36.
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  17. Chen RY, Edwards R, Shaw T, Colledge D, Delaney WE, Isom H, Bowden S, Desmond P, Locarnini SA. Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitro. Hepatology. 2003 Jan; 37(1):27-35.
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  18. Abdelhamed AM, Kelley CM, Miller TG, Furman PA, Isom HC. Rebound of hepatitis B virus replication in HepG2 cells after cessation of antiviral treatment. J Virol. 2002 Aug; 76(16):8148-60.
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  19. Malecki EA, Cable EE, Isom HC, Connor JR. The lipophilic iron compound TMH-ferrocene [(3,5,5-trimethylhexanoyl)ferrocene] increases iron concentrations, neuronal L-ferritin, and heme oxygenase in brains of BALB/c mice. Biol Trace Elem Res. 2002 Apr; 86(1):73-84.
    View in: PubMed
  20. Cable EE, Kuhn BR, Isom HC. Effects of modulators of protein phosphorylation on heme metabolism in human hepatic cells: induction of delta-aminolevulinic synthase mRNA and protein by okadaic acid. DNA Cell Biol. 2002 Apr; 21(4):323-32.
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  21. Bilello JP, Delaney WE, Boyce FM, Isom HC. Transient disruption of intercellular junctions enables baculovirus entry into nondividing hepatocytes. J Virol. 2001 Oct; 75(20):9857-71.
    View in: PubMed
  22. Chin R, Shaw T, Torresi J, Sozzi V, Trautwein C, Bock T, Manns M, Isom H, Furman P, Locarnini S. In vitro susceptibilities of wild-type or drug-resistant hepatitis B virus to (-)-beta-D-2,6-diaminopurine dioxolane and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil. Antimicrob Agents Chemother. 2001 Sep; 45(9):2495-501.
    View in: PubMed
  23. Delaney WE, Edwards R, Colledge D, Shaw T, Torresi J, Miller TG, Isom HC, Bock CT, Manns MP, Trautwein C, Locarnini S. Cross-resistance testing of antihepadnaviral compounds using novel recombinant baculoviruses which encode drug-resistant strains of hepatitis B virus. Antimicrob Agents Chemother. 2001 Jun; 45(6):1705-13.
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  24. Pan WH, Devlin HF, Kelley C, Isom HC, Clawson GA. A selection system for identifying accessible sites in target RNAs. RNA. 2001 Apr; 7(4):610-21.
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  25. Cable EE, Miller TG, Isom HC. Regulation of heme metabolism in rat hepatocytes and hepatocyte cell lines: delta-aminolevulinic acid synthase and heme oxygenase are regulated by different heme-dependent mechanisms. Arch Biochem Biophys. 2000 Dec 15; 384(2):280-95.
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  26. Delaney WE, Miller TG, Isom HC. Use of the hepatitis B virus recombinant baculovirus-HepG2 system to study the effects of (-)-beta-2',3'-dideoxy-3'-thiacytidine on replication of hepatitis B virus and accumulation of covalently closed circular DNA. Antimicrob Agents Chemother. 1999 Aug; 43(8):2017-26.
    View in: PubMed
  27. Crone TM, Schalles SL, Benedict CM, Pan W, Ren L, Loy SE, Isom H, Clawson GA. Growth inhibition by a triple ribozyme targeted to repetitive B2 transcripts. Hepatology. 1999 Apr; 29(4):1114-23.
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  28. Cable EE, Isom HC. Metabolism of 3,5,5-trimethylhexanoyl-ferrocene by rat liver: release of iron from 3,5,5-trimethylhexanoyl-ferrocene by a microsomal, phenobarbital-inducible cytochrome P-450. Drug Metab Dispos. 1999 Feb; 27(2):255-60.
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  29. Delaney WE, Isom HC. Hepatitis B virus replication in human HepG2 cells mediated by hepatitis B virus recombinant baculovirus. Hepatology. 1998 Oct; 28(4):1134-46.
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  30. Cable EE, Connor JR, Isom HC. Accumulation of iron by primary rat hepatocytes in long-term culture: changes in nuclear shape mediated by non-transferrin-bound forms of iron. Am J Pathol. 1998 Mar; 152(3):781-92.
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  31. Cable EE, Isom HC. Exposure of primary rat hepatocytes in long-term DMSO culture to selected transition metals induces hepatocyte proliferation and formation of duct-like structures. Hepatology. 1997 Dec; 26(6):1444-57.
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  32. Reeder MK, Isom HC. Effect of transforming growth factor beta on rat hepatocyte cell lines depends upon the state of tumorigenic progression. Cell Growth Differ. 1996 Apr; 7(4):449-60.
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  33. Guilhot S, Miller T, Cornman G, Isom HC. Apoptosis induced by tumor necrosis factor-alpha in rat hepatocyte cell lines expressing hepatitis B virus. Am J Pathol. 1996 Mar; 148(3):801-14.
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  34. Bour ES, Ward LK, Cornman GA, Isom HC. Tumor necrosis factor-alpha-induced apoptosis in hepatocytes in long-term culture. Am J Pathol. 1996 Feb; 148(2):485-95.
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  35. Clawson GA, Ren L, Isom HC. Nuclear scaffold-associated protease: in situ nuclear localization and effects of a protease inhibitor on growth and morphology of a ras-transformed hepatocyte cell line. Hepatology. 1995 Oct; 22(4 Pt 1):1230-5.
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  36. Kempe KC, Isom HC, Greene FE. Responsiveness of an SV40-immortalized hepatocyte cell line to growth hormone. Biochem Pharmacol. 1995 Apr 18; 49(8):1091-8.
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  37. Serra R, Carbonetto S, Lord M, Isom HC. Transforming growth factor beta 1 suppresses transformation in hepatocytes by regulating alpha 1 beta 1 integrin expression. Cell Growth Differ. 1994 May; 5(5):509-17.
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  38. Hu J, Isom HC. Suppression of albumin enhancer activity by H-ras and AP-1 in hepatocyte cell lines. Mol Cell Biol. 1994 Mar; 14(3):1531-43.
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  39. Serra R, Isom HC. Stimulation of DNA synthesis and protooncogene expression in primary rat hepatocytes in long-term DMSO culture. J Cell Physiol. 1993 Mar; 154(3):543-53.
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  40. Serra R, Verderame MF, Isom HC. Transforming growth factor beta 1 partially suppresses the transformed phenotype of ras-transformed hepatocytes. Cell Growth Differ. 1992 Oct; 3(10):693-704.
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  41. Hu JM, Camper SA, Tilghman SM, Miller T, Georgoff I, Serra R, Isom HC. Functional analyses of albumin expression in a series of hepatocyte cell lines and in primary hepatocytes. Cell Growth Differ. 1992 Sep; 3(9):577-88.
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  42. Isom HC, Woodworth CD, Meng Y, Kreider J, Miller T, Mengel L. Introduction of the ras oncogene transforms a simian virus 40-immortalized hepatocyte cell line without loss of expression of albumin and other liver-specific genes. Cancer Res. 1992 Feb 15; 52(4):940-8.
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  43. Isom H, Kitchingman G, Roy-Burman P, Fausto N, Padarathsingh M. Workshop report from the Division of Research Grants, National Institutes of Health. The role of chromosome rearrangements, deletions, and point mutations in cancer--a Pathology B Study Section workshop. Cancer Res. 1991 Oct 1; 51(19):5440-4.
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  44. Griffith BP, Chen M, Isom HC. Role of primary and secondary maternal viremia in transplacental guinea pig cytomegalovirus transfer. J Virol. 1990 May; 64(5):1991-7.
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  45. Yin CY, Gao M, Isom HC. Guinea pig cytomegalovirus immediate-early transcription. J Virol. 1990 Apr; 64(4):1537-48.
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  46. Griffith BP, Isom HC, Lavallee JT. Cellular localization of cytomegalovirus nucleic acids in guinea pig salivary glands by in situ hybridization. J Virol Methods. 1990 Feb; 27(2):145-57.
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  47. Isom HC, Yin CY. Guinea pig cytomegalovirus gene expression. Curr Top Microbiol Immunol. 1990; 154:101-21.
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  48. Patel NU, Jameel S, Isom H, Siddiqui A. Interactions between nuclear factors and the hepatitis B virus enhancer. J Virol. 1989 Dec; 63(12):5293-301.
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  49. Liao WS, Ma KT, Woodworth CD, Mengel L, Isom HC. Stimulation of the acute-phase response in simian virus 40-hepatocyte cell lines. Mol Cell Biol. 1989 Jul; 9(7):2779-86.
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  50. Hengst JA, Georgoff I, Isom HC, Jacob ST. Association of newly synthesized poly(A) polymerase with four distinct polypeptides. J Biol Chem. 1988 Dec 25; 263(36):19270-3.
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  51. Woodworth CD, Kreider JW, Mengel L, Miller T, Meng YL, Isom HC. Tumorigenicity of simian virus 40-hepatocyte cell lines: effect of in vitro and in vivo passage on expression of liver-specific genes and oncogenes. Mol Cell Biol. 1988 Oct; 8(10):4492-501.
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  52. Cammisa HM, Isom HC, Greene FE. Hormonal regulation of pseudocholinesterase activity in cultured rat hepatocytes. Endocrinology. 1988 Mar; 122(3):991-6.
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  53. Woodworth CD, Isom HC. Transformation of differentiated rat hepatocytes with adenovirus and adenovirus DNA. J Virol. 1987 Nov; 61(11):3570-9.
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  54. Woodworth CD, Isom HC. Regulation of albumin gene expression in a series of rat hepatocyte cell lines immortalized by simian virus 40 and maintained in chemically defined medium. Mol Cell Biol. 1987 Oct; 7(10):3740-8.
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  55. Sha M, Griffith BP, Raveh D, Isom HC, Ward DC, Hsiung GD. Detection of guinea pig cytomegalovirus nucleic acids in cultured cells with biotin-labelled hybridization probes. Virus Res. 1987 Jan; 6(4):317-29.
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  56. Woodworth C, Secott T, Isom HC. Transformation of rat hepatocytes by transfection with simian virus 40 DNA to yield proliferating differentiated cells. Cancer Res. 1986 Aug; 46(8):4018-26.
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  57. Isom HC, Secott T, Georgoff I, Woodworth C, Mummaw J. Maintenance of differentiated rat hepatocytes in primary culture. Proc Natl Acad Sci U S A. 1985 May; 82(10):3252-6.
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  58. Gao M, Isom HC. Characterization of the guinea pig cytomegalovirus genome by molecular cloning and physical mapping. J Virol. 1984 Nov; 52(2):436-47.
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  59. Isom HC, Georgoff I. Quantitative assay for albumin-producing liver cells after simian virus 40 transformation of rat hepatocytes maintained in chemically defined medium. Proc Natl Acad Sci U S A. 1984 Oct; 81(20):6378-82.
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  60. Georgoff I, Secott T, Isom HC. Effect of simian virus 40 infection on albumin production by hepatocytes cultured in chemically defined medium and plated on collagen and non-collagen attachment surfaces. J Biol Chem. 1984 Aug 10; 259(15):9595-602.
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  61. Isom HC, Gao M, Wigdahl B. Characterization of guinea pig cytomegalovirus DNA. J Virol. 1984 Feb; 49(2):426-36.
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  62. Isom HC, Mummaw J, Kreider JW. Malignant transformation of guinea pig cells after exposure to ultraviolet-irradiated guinea pig cytomegalovirus. Virology. 1983 Apr 30; 126(2):693-700.
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  63. Isom HC, Liao WS, Taylor JM, Willwerth GE, Eadline TS. Rapid and selective shutoff of plasma protein production in herpes simplex virus type 2-infected hepatoma cells. Virology. 1983 Apr 30; 126(2):548-62.
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  64. Wigdahl BL, Isom HC, De Clercq E, Rapp F. Activation of herpes simplex virus (HSV) type 1 genome by temperature-sensitive mutants of HSV type 2. Virology. 1982 Jan 30; 116(2):468-79.
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  65. Wigdahl BL, Isom HC, Rapp F. Repression and activation of the genome of herpes simplex viruses in human cells. Proc Natl Acad Sci U S A. 1981 Oct; 78(10):6522-6.
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  66. Isom HC, Tevethia MJ, Kreider JW. Tumorigenicity of simian virus 40-transformed rat hepatocytes. Cancer Res. 1981 Jun; 41(6):2126-34.
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  67. Colberg-Poley AM, Isom HC, Rapp F. Involvement of an early human cytomegalovirus function in reactivation of quiescent herpes simplex virus type 2. J Virol. 1981 Mar; 37(3):1051-9.
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  68. Isom HC, Tevethia MJ, Taylor JM. Transformation of isolated rat hepatocytes with simian virus 40. J Cell Biol. 1980 Jun; 85(3):651-9.
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  69. Isom HC. DNA synthesis in isolated hepatocytes infected with herpesviruses. Virology. 1980 May; 103(1):199-216.
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  70. Isom HC, Tevethia MJ, Taylor JM. Properties of simian virus 40 (SV40)-transformed hepatocytes. Ann N Y Acad Sci. 1980; 349:391-2.
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  71. Colberg-Poley AM, Isom HC, Rapp F. Reactivation of herpes simplex virus type 2 from a quiescent state by human cytomegalovirus. Proc Natl Acad Sci U S A. 1979 Nov; 76(11):5948-51.
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  72. Isom HC, Pegg AE. Inhibition of cytomegalovirus-stimulated human cell ornithine decarboxylase by alpha-difluoromethylornithine. Biochim Biophys Acta. 1979 Oct 25; 564(3):402-13.
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  73. Colberg-Poley AM, Isom H, Rapp F. Experimental HSV latency using phosphonoacetic acid. Proc Soc Exp Biol Med. 1979 Oct; 162(1):235-7.
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  74. Isom HC, Backstrom JT. Aberrant regulation of ornithine decarboxylase by serum, putrescine, and spermidine in cytomegalovirus-transformed human cells. Cancer Res. 1979 Mar; 39(3):864-9.
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  75. Isom HC. Stimulation of ornithine decarboxylase by human cytomegalovirus. J Gen Virol. 1979 Feb; 42(2):265-78.
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  76. Isom H, Colberg A, Reed C, Rapp F. Conditions required for induction of murine p30 by herpes simplex virus. Int J Cancer. 1978 Jul 15; 22(1):22-7.
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  77. Isom HC, Pizer LI. Growth dependence of phosphoglyceric acid dehydrogenase activity in cultured rat liver cells. J Cell Physiol. 1978 May; 95(2):139-50.
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  78. Isom HC, DeMoss RD. Pyridoxal 5'-phosphate and analogs as probes of coenzyme-protein interaction in Baccillus alvei tryptophanase. Biochemistry. 1975 Sep 23; 14(19):4291-7.
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  79. Isom HC, DeMoss RD. Structural role of pyridoxal 5'-phosphate, pyridoxal 5'-phosphate analogs, and other agents in the association of subunits of Bacillus alvei apotryptophanase. Biochemistry. 1975 Sep 23; 14(19):4298-304.
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  80. Lovett PS, Pizer LI, Isom HC. Enzymatic defects in three genetic classes of serine-requiring mutants of Bacillus pumilus. J Bacteriol. 1973 Nov; 116(2):1075-8.
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