Felsher Lab In the Division of Oncology

Felsher Laboratory Research

Our laboratory investigates how oncogenes initiate and sustain tumorigenesis. We have developed model systems whereby we can conditionally activate oncogenes in normal human and mouse cells in tissue culture or in specific tissues of transgenic mice.

In particular, using the tetracycline regulatory system, we have generated a conditional model system for MYC-induce hematopoietic tumors. Using the tet system, we have shown that cancers caused by the conditional over-expression of the MYC proto-oncogene regress with its inactivation. Thus, even though cancer is a multi-step process, the inactivation of one oncogene can be sufficient to induce tumor regression. Now, we are using these model systems to address three questions:

  1. How do oncogenes initiate tumorigenesis?
  2. How does oncogene inactivation cause tumor regression?
  3. How do tumors escape dependence on oncogenes?
Conditional Tet System
Felsher DW 2003  Vol 3, pp. 375  Nature Reviews Cancer
The Tetracycline-dependent regulatory system used by the Felsher lab was developed by Gossen and Bujard. The effector is a sequence that encodes the tetracycline transactivator protein, (or tTA). TTA proteins dimerize, and this dimer is capable of specifically binding tetracycline (or doxycycline, which we call dox, and also, these dimers can bind tetracycline operator sequences (called tet-o-secquences). In the absence of doxycycline, tTA dimers bind specifically to a concatamer of seven tetO sequences (7X tet-o) and activate oncogene transcription from the minimal TATA promoter. Following binding to dox, tTA dimers undergo conformational changes that result in loss of sequence-specific DNA binding, and the oncogene is no longer activated. Therefore, with the tetracycline system, we can, at will, activate and subsequently inactivate, oncogenes in our mice as many times as we like. Oncogene inactivation is achieved by simply treating the mice with nanogram concentrations of doxycycline.

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