P27kip1 as an early effector of pRB function

  • Zhu, Liang (PI)

Project: Research project

Project Details

Description

DESCRIPTION: (Adapted from the investigator's abstract) The tumor suppressor
retinoblastoma protein inhibits cell proliferation when re-expressed in
pRB-deficient tumor cells. Our objective is to identify the molecular
mechanisms underlying this function of pRB. The currently most accepted model
for pRB function is that pRB forms complexes with the transcription factor E2F
to repress the expression of certain genes whose encoded proteins promote cell
proliferation. The lack of these growth promoting proteins will then pose a
block to the initiation of DNA replication. This latter aspect of the model
however remains to be tested experimentally. We have discovered that, in time
course experiments after controlled re-expression of pRB in pRB-deficient tumor
cells, protein levels of cyclin EfCdk2 and cyclin A/Cdk2, perhaps the most
important repression targets of pRB, declined after the onset of GI cell cycle
arrest. The kinase activities of these complexes however were inhibited with
the onset of Gi arrest by an early increase in the protein levels of the
cyclin-dependent kinase inhibitor p27Kipl. We therefore hypothesize that p27 is
an early effector of pRB function. In this application, we will achieve two
specific aims to test this hypothesis. In aim 1, we will determine the role of
p27 level increase in pRB-mediated 01 arrest. Our second aim is to determine
the mechanisms by which pRB induces p27 levels in the cell. Although not found
mutated in human tumors, p27 has been implicated in tumor prognosis by the fact
that more aggressive tumors contain lower levels of p27 due to active protein
degradation. Successful completion of the proposed studies will not only
provide new knowledge about the functional mechanism of pRB but also reveal a
new mechanism for the involvement of p27 in cancer. A better understanding of
the complex regulatory networks linking various negative regulators of cell
proliferation has the great potential of revealing vulnerable steps for
therapeutic targeting in the treatment of cancer, a long-term objective of our
research.
StatusFinished
Effective start/end date4/1/013/31/06

Funding

  • National Cancer Institute: $263,222.00
  • National Cancer Institute: $263,813.00
  • National Cancer Institute: $263,025.00
  • National Cancer Institute: $263,025.00

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