REGULATION OF MITOGENIC CYTOKINE INDUCED APOPTOSIS

Project Details

Description

DESCRIPTION (Adapted from Investigator's Abstract). Cell proliferation requires
coordinated activation of genes involved in cell cycle progression as well as
genes for maintaining cell viability. Without the latter, progression through
the cell cycle will lead to apoptosis. The applicant has investigated the
relationship between cell proliferation and apoptosis by activating cells with
mitogenic cytokines and growth factors in the presence or absence of serum.
When stimulated with cytokines or growth factors in the absence of serum,
several cell types underwent apoptosis, a phenomenon referred to as
cytokine-promoted apoptosis (CPA). Interestingly, in this system, serum induces
expression of cell survival genes such as bcl-2 while mitogenic cytokines
induce expression of pro-apoptotic genes including bax and c-myc in the absence
of serum. By transfecting cells with an expression cDNA library, followed by
double selection with CPA and neomycin, the applicant has identified a novel
cell survival gene SRG-1. This gene is located on human chromosome 1 at
1p34-1p36.1, a location implicated in tumorigenesis in a number of cell
lineages. SRG-1 encodes a putative protein of 154 amino acids. Stable
transfection of SRG-1 to BAF/B03 cells confers resistance to CPA. SRG-1 also
inhibits c-myc-driven apoptosis in serum-deprived fibroblasts. SRG-1 is highly
expressed in some tumors and in activated T cells, but is not detected in most
normal tissues, except liver and spleen. Based on these preliminary data, the
applicant proposes to determine the mechanism underlying CPA and to
characterize the role of SRG-1 in regulating CPA. The applicant hypothesizes
that cytokines induce expression of genes like c-myc, which predispose cells to
proliferation or undergo apoptosis. The ultimate outcome is determined by the
presence or absence of second signals which activate cell survival genes such
as Bcl-2 and SRG-1. The following aims are designed to test the hypothesis: 1)
The applicant will establish the role of c-myc, its upstream Realtor E2F1 and a
downstream target cdc25A in CPA. These genes will be modulated by transfection
of the cDNA in anti-sense and dominant negative forms under the control of the
ecdysone-inducible promoter. 2) The applicant will determine the role of SRG-1
in CPA by examining its expression pattern, cell survival functions, and
interacting proteins. The completion of the proposed experiments may improve
the understanding of the regulation of cellular homeostasis during
inflammation, development, aging and tumorigenesis.
StatusFinished
Effective start/end date7/1/994/30/04

Funding

  • National Cancer Institute: $157,143.00

ASJC

  • Genetics
  • Cell Biology

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