Trans acting function of the v and c Rel oncoproteins

Project Details

Description

DESCRIPTION: (Adapted from the investigator's abstract): The v-Rel oncoprotein
of the highly oncogenic retrovirus reticuloendotheliosis virus strain T (Rev-T)
induces aggressive and fatal leukemia/lymphoma in chickens and transgenic mice.
Its cellular homolog c-Rel is essential for lymphoid cell survival and
proliferation, and for immune and inflammatory responses. Both v-Rel and c-Rel
belong to the Rel/NF-KB family of transcription factors. Members of this family
share extensive sequence similarity in their N-terminal Rel-homology domain,
activate the transcription of genes linked to kB DNA sites and exhibit related
biological activities. Chromosomal amplification, rearrangement, overexpression
and/or constitutive activation of rel/nf-kb genes are implicated in many human
hematopoietic tumors such as lymphoma, leukemia, myeloma and Hodgkin's disease.
Aberrant rel/nf-kb genes and activity are also observed in solid tumors such as
lung, breast, colon, ovarian and prostate carcinomas. It is therefore important
to elucidate how the ReI/NF-kB proteins function in oncogenesis and to
understand their regulation. While most vertebrate cellular ReI/NF-kB factors
have been implicated in human cancer, none of them is acutely oncogenic when
expressed in primary cells or in transgenic mice. The retroviral oncoprotein
v-Rel therefore provides an excellent and unique tool tO directly address the
function and regulation of these factors in the physiologically relevant
context of primary lymphoid cells. Our studies of the past few years support
the notion that lymphoid cell transformation by v-Rel results from the
activation of specific cellular genes, and point to its regulation by
phosphorylation. Our analyses also demonstrated an absolute correlation between
the anti-apoptotic and oncogenic activities of v-Rel transactivation mutants.
This application for continuation of support will investigate how
v-Rel-mediated transactivation effects cell survival, proliferation and
oncogenesis (Aim. 1). Experiments are also proposed to further characterize the
transactivation function of v-Rel and c-Rel and its mode of action (Aim. 2),
and to explore the role of phosphorylation in its regulation (Aim. 3).
Collectively, these studies will clarify the pathways through which the viral
oncoprotein v-Rel functions in malignant lymphoid cell transformation. This
work will also provide invaluable insights into the events necessary for the
oncogenic conversion of cellular ReI/NF-KB factors.
StatusFinished
Effective start/end date7/5/966/30/07

Funding

  • National Cancer Institute
  • National Cancer Institute: $231,486.00
  • National Cancer Institute: $265,542.00
  • National Cancer Institute: $265,383.00
  • National Cancer Institute: $265,696.00
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute: $265,220.00
  • National Cancer Institute: $265,845.00
  • National Cancer Institute

ASJC

  • Genetics
  • Molecular Biology
  • Cancer Research

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