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James George Rheinwald, Ph.D.

TitleAssociate Professor of Dermatology
InstitutionBrigham and Women's Hospital
DepartmentDermatology
AddressBrigham and Women's Hospital
Dermatology, HIM-664
77 Avenue Louis Pasteur
Boston MA 02115
Phone617/525-5553
Fax617/525-5571

 Overview 
 overview
The research interest of the Rheinwald laboratory is to understand the mechanisms that regulate growth, differentiation, motility, and malignant transformation of epithelial cells. Our major focus is the keratinocyte—the cell type that forms stratified squamous epithelial tissues, which include the epidermis and the oral, corneal, conjunctival, esophageal, and exocervical epithelia. We also study prostate epithelial cells, pleural and peritoneal mesothelial cells, sweat gland myoepithelial cells, and somatic epithelial cells derived from embryonic stem cells. We use human cell culture model systems and a genetic engineering approach: using retroviral and lentiviral expression and shRNA vectors to investigate the roles of specific proteins in key cellular mechanisms. Our lab is currently devoting its effort to two projects.
The first seeks to understand the mechanisms and associated markers of neoplastic progression in the epidermis and oral epithelium toward squamous cell carcinoma (SCC). We have identified p16INK4A and Laminin ?2 chain overexpression in late stage premalignant dysplastic lesions of these epithelia in vivo and are investigating SCC cells and engineered keratinocyte models to find cause and effect relationships between hyperstimulation of mitogen and survival signal pathways and Laminin ?2 dysregulation. These studies seek to identify prognostic immunohistochemical markers and potential targets for kinase inhibitors to identify and treat premalignant lesions at an early stage, before they become large, deeply invasive, and incurable cancers.
The second project seeks to understand the role of the transcriptional regulator p63 in determining expression of a set of cell-substratum adhesion proteins and growth control mechanisms that are shared by a large family of epithelial cell types and play important roles in the maintenance of tissue stem cell character. We are engineering cells to stably express or to knock down expression of p63 to determine the consequences to cell type identity, patterns of gene and protein expression, and growth control mechanisms.

Dr. Rheinwald also directs a Cell Culture Core. The Core provides well-characterized primary human cell lines, squamous cell carcinoma-derived, TERT-immortalized, and other engineered cell lines from our large cryopreserved collection. The Core also provides other services, as described on the Rheinwald lab website: http://rheinwaldlab.bwh.harvard.edu.


 Research 
 research resources
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Cell Culture and Microscopy Core (BWH) - Chemical reagents (1), Core services (7) and Instruments (1)

 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. Degen M, Barron P, Natarajan E, Widlund HR, Rheinwald JG. RSK Activation of Translation Factor eIF4B Drives Abnormal Increases of Laminin ?2 and MYC Protein during Neoplastic Progression to Squamous Cell Carcinoma. PLoS One. 2013; 8(10):e78979.
    View in: PubMed
  2. Pinto AP, Degen M, Barron P, Crum CP, Rheinwald JG. Phosphorylated S6 as an immunohistochemical biomarker of vulvar intraepithelial neoplasia. Mod Pathol. 2013 Nov; 26(11):1498-507.
    View in: PubMed
  3. Degen M, Natarajan E, Barron P, Widlund HR, Rheinwald JG. MAPK/ERK-dependent translation factor hyperactivation and dysregulated laminin ?2 expression in oral dysplasia and squamous cell carcinoma. Am J Pathol. 2012 Jun; 180(6):2462-78.
    View in: PubMed
  4. Wei W, Barron PD, Rheinwald JG. Modulation of TGF-ß-inducible hypermotility by EGF and other factors in human prostate epithelial cells and keratinocytes. In Vitro Cell Dev Biol Anim. 2010 Dec; 46(10):841-55.
    View in: PubMed
  5. Zhang W, Choi J, Zeng W, Rogers SA, Alyea EP, Rheinwald JG, Canning CM, Brusic V, Sasada T, Reinherz EL, Ritz J, Soiffer RJ, Wu CJ. Graft-versus-leukemia antigen CML66 elicits coordinated B-cell and T-cell immunity after donor lymphocyte infusion. Clin Cancer Res. 2010 May 15; 16(10):2729-39.
    View in: PubMed
  6. Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, Khalil A, Rheinwald JG, Hochedlinger K. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature. 2009 Aug 27; 460(7259):1145-8.
    View in: PubMed
  7. Dabelsteen S, Hercule P, Barron P, Rice M, Dorsainville G, Rheinwald JG. Epithelial cells derived from human embryonic stem cells display p16INK4A senescence, hypermotility, and differentiation properties shared by many P63+ somatic cell types. Stem Cells. 2009 Jun; 27(6):1388-99.
    View in: PubMed
  8. Natarajan E, Omobono JD, Guo Z, Hopkinson S, Lazar AJ, Brenn T, Jones JC, Rheinwald JG. A keratinocyte hypermotility/growth-arrest response involving laminin 5 and p16INK4A activated in wound healing and senescence. Am J Pathol. 2006 Jun; 168(6):1821-37.
    View in: PubMed
  9. Iuchi S, Dabelsteen S, Easley K, Rheinwald JG, Green H. Immortalized keratinocyte lines derived from human embryonic stem cells. Proc Natl Acad Sci U S A. 2006 Feb 7; 103(6):1792-7.
    View in: PubMed
  10. Natarajan N, Omobono JD II, Guo Z, Hopkinson S, Lazar AJF, Brenn T, Jones JC, Rheinwald JG. A keratinocyte hypermotility/growth arrest response involving Laminin 5 and p16INK4A activated in wound healing and senescence. Am J Path. 2006; (168):1821-1837.
  11. Natarajan E, Omobono JD, Jones JC, Rheinwald JG. Co-expression of p16INK4A and laminin 5 by keratinocytes: a wound-healing response coupling hypermotility with growth arrest that goes awry during epithelial neoplastic progression. J Investig Dermatol Symp Proc. 2005 Nov; 10(2):72-85.
    View in: PubMed
  12. Gordon GJ, Rockwell GN, Jensen RV, Rheinwald JG, Glickman JN, Aronson JP, Pottorf BJ, Nitz MD, Richards WG, Sugarbaker DJ, Bueno R. Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling. Am J Pathol. 2005 Jun; 166(6):1827-40.
    View in: PubMed
  13. Natarajan E, Omobono JD, Jones JC, Rheinwald JG. Co-expression of p16INK4A and Laminin 5 by keratinocytes: a wound healing response coupling hypermotility with growth arrest that goes awry during epithelial neoplastic progression. J Invest Dermatol Symposium Proceedings. 2005; (10):72-85.
  14. Kim M, Yang H, Kim SK, Reche PA, Tirabassi RS, Hussey RE, Chishti Y, Rheinwald JG, Morehead TJ, Zech T, Damon IK, Welsh RM, Reinherz EL. Biochemical and functional analysis of smallpox growth factor (SPGF) and anti-SPGF monoclonal antibodies. J Biol Chem. 2004 Jun 11; 279(24):25838-48.
    View in: PubMed
  15. Rheinwald JG. Becoming a scientist: what I learned from Gunny. Biochem Biophys Res Commun. 2003 Dec 5; 312(1):61-4.
    View in: PubMed
  16. Kleine-Lowinski K, Rheinwald JG, Fichorova RN, Anderson DJ, Basile J, Münger K, Daly CM, Rösl F, Rollins BJ. Selective suppression of monocyte chemoattractant protein-1 expression by human papillomavirus E6 and E7 oncoproteins in human cervical epithelial and epidermal cells. Int J Cancer. 2003 Nov 10; 107(3):407-15.
    View in: PubMed
  17. Natarajan E, Saeb M, Crum CP, Woo SB, McKee PH, Rheinwald JG. Co-expression of p16(INK4A) and laminin 5 gamma2 by microinvasive and superficial squamous cell carcinomas in vivo and by migrating wound and senescent keratinocytes in culture. Am J Pathol. 2003 Aug; 163(2):477-91.
    View in: PubMed
  18. Rheinwald JG, Hahn WC, Ramsey MR, Wu JY, Guo Z, Tsao H, De Luca M, Catricalà C, O'Toole KM. A two-stage, p16(INK4A)- and p53-dependent keratinocyte senescence mechanism that limits replicative potential independent of telomere status. Mol Cell Biol. 2002 Jul; 22(14):5157-72.
    View in: PubMed
  19. Verselis SJ, Rheinwald JG, Fraumeni JF, Li FP. Novel p53 splice site mutations in three families with Li-Fraumeni syndrome. Oncogene. 2000 Aug 31; 19(37):4230-5.
    View in: PubMed
  20. Dickson MA, Hahn WC, Ino Y, Ronfard V, Wu JY, Weinberg RA, Louis DN, Li FP, Rheinwald JG. Human keratinocytes that express hTERT and also bypass a p16(INK4a)-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics. Mol Cell Biol. 2000 Feb; 20(4):1436-47.
    View in: PubMed
  21. Schön M, Benwood J, O'Connell-Willstaedt T, Rheinwald JG. Human sweat gland myoepithelial cells express a unique set of cytokeratins and reveal the potential for alternative epithelial and mesenchymal differentiation states in culture. J Cell Sci. 1999 Jun; 112 ( Pt 12):1925-36.
    View in: PubMed
  22. Murphy JE, Rheinwald JG. Intraperitoneal injection of genetically modified, human mesothelial cells for systemic gene therapy. Hum Gene Ther. 1997 Nov 1; 8(16):1867-79.
    View in: PubMed
  23. Fichorova RN, Rheinwald JG, Anderson DJ. Generation of papillomavirus-immortalized cell lines from normal human ectocervical, endocervical, and vaginal epithelium that maintain expression of tissue-specific differentiation proteins. Biol Reprod. 1997 Oct; 57(4):847-55.
    View in: PubMed
  24. Schrager HM, Rheinwald JG, Wessels MR. Hyaluronic acid capsule and the role of streptococcal entry into keratinocytes in invasive skin infection. J Clin Invest. 1996 Nov 1; 98(9):1954-8.
    View in: PubMed
  25. Schön M, Rheinwald JG. A limited role for retinoic acid and retinoic acid receptors RAR alpha and RAR beta in regulating keratin 19 expression and keratinization in oral and epidermal keratinocytes. J Invest Dermatol. 1996 Sep; 107(3):428-38.
    View in: PubMed
  26. Park S, Schalling M, Bernard A, Maheswaran S, Shipley GC, Roberts D, Fletcher J, Shipman R, Rheinwald J, Demetri G, et al. The Wilms tumour gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma. Nat Genet. 1993 Aug; 4(4):415-20.
    View in: PubMed
  27. Lindberg K, Brown ME, Chaves HV, Kenyon KR, Rheinwald JG. In vitro propagation of human ocular surface epithelial cells for transplantation. Invest Ophthalmol Vis Sci. 1993 Aug; 34(9):2672-9.
    View in: PubMed
  28. Crowe DL, Hu L, Gudas LJ, Rheinwald JG. Variable expression of retinoic acid receptor (RAR beta) mRNA in human oral and epidermal keratinocytes; relation to keratin 19 expression and keratinization potential. Differentiation. 1991 Dec; 48(3):199-208.
    View in: PubMed
  29. Hu L, Crowe DL, Rheinwald JG, Chambon P, Gudas LJ. Abnormal expression of retinoic acid receptors and keratin 19 by human oral and epidermal squamous cell carcinoma cell lines. Cancer Res. 1991 Aug 1; 51(15):3972-81.
    View in: PubMed
  30. Rheinwald JG, Tubo R, Zenzie B, O'Connell T, Terpstra A. Mitogen-independence and autocrine growth factor secretion displayed by human mesothelioma cells and oncogene-transfected mesothelial cells. Rhim JS, Dritschilo A, eds. Neoplastic Transformation in Human Cell Culture. 1991; 359-366.
  31. O'Connell TM, Rheinwald JG. The biology of normal, malignant, and oncogene transfected human mesothelial cells in culture. Brinkley W, Lechner J, Harris C, eds. Cellular and Molecular Aspects of Fiber Carcinogenesis. 1991; 55-65.
  32. Lindberg K, Rheinwald JG. Three distinct keratinocyte subtypes identified in human oral epithelium by their patterns of keratin expression in culture and in xenografts. Differentiation. 1990 Dec; 45(3):230-41.
    View in: PubMed
  33. Demetri GD, Ernst TJ, Pratt ES, Zenzie BW, Rheinwald JG, Griffin JD. Expression of ras oncogenes in cultured human cells alters the transcriptional and posttranscriptional regulation of cytokine genes. J Clin Invest. 1990 Oct; 86(4):1261-9.
    View in: PubMed
  34. Henrard DR, Thornley AT, Brown ML, Rheinwald JG. Specific effects of ras oncogene expression on the growth and histogenesis of human epidermal keratinocytes. Oncogene. 1990 Apr; 5(4):475-81.
    View in: PubMed
  35. Rheinwald, JG. Aberrations of keratinocyte growth and differentiation associated with oral squamous cell carcinoma. Fee WE, ed. Head and Neck Cancer. 1990; 2:74-76.
  36. Cicila GT, O'Connell TM, Hahn WC, Rheinwald JG. Cloned cDNA sequence for the human mesothelial protein 'mesosecrin' discloses its identity as a plasminogen activator inhibitor (PAI-1) and a recent evolutionary change in transcript processing. J Cell Sci. 1989 Sep; 94 ( Pt 1):1-10.
    View in: PubMed
  37. Demetri GD, Zenzie BW, Rheinwald JG, Griffin JD. Expression of colony-stimulating factor genes by normal human mesothelial cells and human malignant mesothelioma cells lines in vitro. Blood. 1989 Aug 15; 74(3):940-6.
    View in: PubMed
  38. Rollins BJ, O'Connell TM, Bennett G, Burton LE, Stiles CD, Rheinwald JG. Environment-dependent growth inhibition of human epidermal keratinocytes by recombinant human transforming growth factor-beta. J Cell Physiol. 1989 Jun; 139(3):455-62.
    View in: PubMed
  39. Rheinwald JG. Human epidermal keratinocyte cell culture and xenograft systems: applications in the detection of potential chemical carcinogens and the study of epidermal transformation. Prog Clin Biol Res. 1989; 298:113-25.
    View in: PubMed
  40. Rheinwald, JG. Methods for clonal growth and serial cultivation of normal human epidermal keratinocytes and mesothelial cells. Baserga R, ed. Cell Growth and Division: A Practical Approach. 1989; 81-94.
  41. Pardee AB. Rheinwald JG. Normal Growth and Differentiation. Kelley WN, ed. Textbook of Internal Medicine. 1989; 1126-1129.
  42. Rheinwald JG, Lindberg K, Brown ME, O'Connell TM. Intrinsic differences in histogenic potential and keratin regulation among oral epithelial cell types and dysregulation of keratin 19 in oral premalignant dysplasia. Osborn M, Weber K, eds. Current Communications in Molecular Biology: Cytoskeletal Proteins in Tumor Diagnosis. 1989; 107-113.
  43. Lindberg K, Rheinwald JG. Suprabasal 40 kd keratin (K19) expression as an immunohistologic marker of premalignancy in oral epithelium. Am J Pathol. 1989 Jan; 134(1):89-98.
    View in: PubMed
  44. Pardee AB, Rheinwald JG. Cell Growth Control and Cancer. LaFond RE, ed. Cancer: The Outlaw Cell. 1988; 19-36.
  45. Tubo RA, Rheinwald JG. Normal human mesothelial cells and fibroblasts transfected with the EJras oncogene become EGF-independent, but are not malignantly transformed. Oncogene Res. 1987 Sep-Oct; 1(4):407-21.
    View in: PubMed
  46. Rheinwald JG, Jorgensen JL, Hahn WC, Terpstra AJ, O'Connell TM, Plummer KK. Mesosecrin: a secreted glycoprotein produced in abundance by human mesothelial, endothelial, and kidney epithelial cells in culture. J Cell Biol. 1987 Feb; 104(2):263-75.
    View in: PubMed
  47. Rheinwald JG, O'Connell TM. Intermediate filament proteins as distinguishing markers of cell type and differentiated state in cultured human urinary tract epithelia. Ann N Y Acad Sci. 1985; 455:259-67.
    View in: PubMed
  48. La Rocca PJ, Rheinwald JG. Anchorage-independent growth of normal human mesothelial cells: a sensitive bioassay for EGF which discloses the absence of this factor in fetal calf serum. In Vitro Cell Dev Biol. 1985 Jan; 21(1):67-72.
    View in: PubMed
  49. Allen-Hoffmann BL, Rheinwald JG. Polycyclic aromatic hydrocarbon mutagenesis of human epidermal keratinocytes in culture. Proc Natl Acad Sci U S A. 1984 Dec; 81(24):7802-6.
    View in: PubMed
  50. LaRocca PJ, Rheinwald JG. Coexpression of simple epithelial keratins and vimentin by human mesothelium and mesothelioma in vivo and in culture. Cancer Res. 1984 Jul; 44(7):2991-9.
    View in: PubMed
  51. Weichselbaum R, Dahlberg W, Little JB, Ervin TJ, Miller D, Hellman S, Rheinwald JG. Cellular X-ray repair parameters of early passage squamous cell carcinoma lines derived from patients with known responses to radiotherapy. Br J Cancer. 1984 May; 49(5):595-601.
    View in: PubMed
  52. Nadakavukaren KK, Summerhayes IC, Salcedo BF, Rheinwald JG, Chen LB. A monoclonal antibody recognizing a keratin filament protein in a subset of transitional and glandular epithelia. Differentiation. 1984; 27(3):209-20.
    View in: PubMed
  53. Rheinwald JG, O'Connell TM, Connell ND, Rybak SM, Allen Hoffmann BL, LaRocca PJ, Wu Y J, Rehwoldt SM. Expression of specific keratin subsets and vimentin in normal human epithelial cells: a function of cell type and conditions of growth during serial culture. Cancer Cells 1/The Transformed Phenotype. 1984; 217-227.
  54. Connell ND, Rheinwald JG. Regulation of the cytoskeleton in mesothelial cells: reversible loss of keratin and increase in vimentin during rapid growth in culture. Cell. 1983 Aug; 34(1):245-53.
    View in: PubMed
  55. Kim KH, Rheinwald JG, Fuchs EV. Tissue specificity of epithelial keratins: differential expression of mRNAs from two multigene families. Mol Cell Biol. 1983 Apr; 3(4):495-502.
    View in: PubMed
  56. Rheinwald JG, Germain E, Beckett MA. Expression of keratins and envelope proteins in normal and malignant human keratinocytes and mesothelial cells. Harris CC, ed. Human Carcinogenesis. 1983; 85-96.
  57. Wu YJ, Parker LM, Binder NE, Beckett MA, Sinard JH, Griffiths CT, Rheinwald JG. The mesothelial keratins: a new family of cytoskeletal proteins identified in cultured mesothelial cells and nonkeratinizing epithelia. Cell. 1982 Dec; 31(3 Pt 2):693-703.
    View in: PubMed
  58. Rheinwald JG. Human squamous cell carcinoma in culture: a defect in terminal differentiation and its relation to malignancy. Natl Cancer Inst Monogr. 1982; 60:133-8.
    View in: PubMed
  59. Didinsky JB, Rheinwald JG. Failure of hydrocortisone or growth factors to influence the senescence of fibroblasts in a new culture system for assessing replicative lifespan. J Cell Physiol. 1981 Oct; 109(1):171-9.
    View in: PubMed
  60. Wu YJ, Rheinwald JG. A new small (40 kd) keratin filament protein made by some cultured human squamous cell carcinomas. Cell. 1981 Sep; 25(3):627-35.
    View in: PubMed
  61. Rheinwald JG, Beckett MA. Tumorigenic keratinocyte lines requiring anchorage and fibroblast support cultures from human squamous cell carcinomas. Cancer Res. 1981 May; 41(5):1657-63.
    View in: PubMed
  62. Rheinwald JG, Beckett MA. Defective terminal differentiation in culture as a consistent and selectable character of malignant human keratinocytes. Cell. 1980 Nov; 22(2 Pt 2):629-32.
    View in: PubMed
  63. Rheinwald JG. Serial cultivation of normal human epidermal keratinocytes. Methods Cell Biol. 1980; 21A:229-54.
    View in: PubMed
  64. Rheinwald JG. The role of terminal differentiation in the finite culture lifetime of the human epidermal keratinocyte. Int Rev Cytol Suppl. 1979; (10):25-33.
    View in: PubMed
  65. Rheinwald JG. The role of terminal differentiation in the finite culture lifetime of the human epidermal keratinocyte. Nichols WW, Murphy DG, eds. International Review of Cytology Suppl. 10: Differentiated Cells in Aging Research. 1979; 25-33.
  66. Rheinwald JG, Green H. Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes. Nature. 1977 Feb 3; 265(5593):421-4.
    View in: PubMed
  67. Green H, Rheinwald JG, Sun TT. Properties of an epithelial cell type in culture: the epidermal keratinocyte and its dependence on products of the fibroblast. Prog Clin Biol Res. 1977; 17:493-500.
    View in: PubMed
  68. Rheinwald JG, Green H. Formation of a keratinizing epithelium in culture by a cloned cell line derived from a teratoma. Cell. 1975 Nov; 6(3):317-30.
    View in: PubMed
  69. Rheinwald JG, Green H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell. 1975 Nov; 6(3):331-43.
    View in: PubMed
  70. Rheinwald JG, Green H. Growth of cultured mammalian cells on secondary glucose sources. Cell. 1974 Aug; 2(4):287-93.
    View in: PubMed
  71. Rheinwald JG, Chakrabarty AM, Gunsalus IC. A transmissible plasmid controlling camphor oxidation in Pseudomonas putida. Proc Natl Acad Sci U S A. 1973 Mar; 70(3):885-9.
    View in: PubMed
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