Harvard Medical School


Contact Information:

Channing Laboratory

181 Longwood Ave.

Boston, MA 02115

phone: 617-525-4250

fax: 617-525-4251

 

ekieff@rics.bwh.harvard.edu

Kieff Lab Home

 

Research Summary

Human viruses are responsible for about 20% of human malignancies world-wide and offer unique opportunities for early diagnosis, prevention, and therapeutic intervention. Viruses have relatively simple genomes and effect nearly immediate changes in infected cell signal transduction, transcription, growth, and survival. Therefore studies of virus infection also contribute to current genetics, biochemistry, cell biology, and immunology, as well as virology. Our experiments began with the study of the fundamental mechanisms by which Epstein-Barr Virus, an important causative agent of lymphomas, Hodgkin's Disease and Naso-pharyngeal carcinoma, uniquely and efficiently causes the uncontrolled proliferation and survival of normal human B lymphocytes.

We have discovered that, the virus uses only five genes to cause B cell proliferation. These genes encode nuclear proteins that usurp control over Notch regulated cell promoters, including the c-myc promoter, and an integral membrane protein that constitutively activates CD40 signaling pathways. We are currently investigating the genetics and biochemistry of the molecular and sub-molecular processes through which the viral proteins effect changes in cell signal transduction, transcription, growth, and survival so as to validate targets that can be used in assays to identify chemical inhibitors.

Ongoing projects for fellows and students involve:

  1. Elucidation of the molecular and sub-molecular pathways by which Notch and viral proteins regulate the c-myc promoter. Structural studies of a key viral and cellular interaction site.
  2. Elucidation of the molecular and sub-molecular pathways by which CD40 and a viral protein co-stimulate cell growth and survival.
  3. Proteinomic and cell genetic screens for novel genes in the CD40 and viral protein NF-kB, Junk, and p38 pathways.
  4. Sub-molecular mechanisms by which a viral protein permits episome replication and maintenance.

Selected Publications

Lin J, Johannsen E, Robertson E, Kieff E. Epstein-Barr virus nuclear antigen 3C putative repression domain mediates coactivation of the LMP1 promoter with EBNA-2. J Virol. 2002 Jan;76(1):232-42.

Kang MS, Hung SC, Kieff E. Epstein-Barr virus nuclear antigen 1 activates transcription from episomal but not integrated DNA and does not alter lymphocyte growth. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15233-8.

Hung SC, Kang MS, Kieff E. Maintenance of Epstein-Barr virus (EBV) oriP-based episomes requires EBV-encoded nuclear antigen-1 chromosome-binding domains, which can be replaced by high-mobility group-I or histone H1. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1865-70.

Harada S, Yalamanchili R, Kieff E. Epstein-Barr virus nuclear protein 2 has at least two N-terminal domains that mediate self-association. J Virol. 2001 Mar;75(5):2482-7.

Cahir-McFarland ED, Davidson DM, Schauer SL, Duong J, Kieff E. NF-kappa B inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed lymphoblastoid cells. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6055-60.