Abstract
Prostate apoptosis response-4 (Par-4) is a tumor-suppressor protein that induces apoptosis in cancer cells, but not in normal/immortalized cells. The cancer-specific proapoptotic action of Par-4 is encoded in its centrally located SAC domain. We report here the characterization of a novel mouse model with ubiquitous expression of the SAC domain. Although SAC transgenic mice displayed normal development and life span, they were resistant to the growth of spontaneous, as well as oncogene-induced, autochthonous tumors. Resistance to tumorigenesis was linked to inhibition of nuclear factor-kappaB activity and induction of apoptosis by the SAC domain. Collectively, our findings provide genetic evidence that the SAC domain of Par-4 confers cancer resistance in transgenic mice without compromising normal viability or aging, and may have therapeutic significance.
Highlights
Prostate apoptosis response-4 (Par-4), the product of the proapoptotic gene par-4, was first identified in prostate cancer cells that were induced to undergo apoptosis [1]
The findings of this study indicated that ubiquitous expression of the SAC domain of Par-4 is well tolerated in transgenic mice and does not interfere with the development, fertility, or life span of the animals
Inhibition of pro-cell survival nuclear factor-nB (NF-nB) activity was identified as a mechanism underlying SAC domain–mediated apoptosis of oncogene-expressing cells
Summary
Prostate apoptosis response-4 (Par-4), the product of the proapoptotic gene par-4, was first identified in prostate cancer cells that were induced to undergo apoptosis [1]. Par-4 is a leucine zipper domain protein that is widely expressed in diverse normal and cancerous cell types and tissues [2, 3]. Ectopic Par-4 overexpression is by itself sufficient to induce apoptosis in most cancer cells, but not in normal or immortalized cells [4]. This cancer-selective apoptotic action of Par-4 does not require the leucine zipper domain, which is present at its carboxy terminus [4]. Neither p53 nor PTEN are directly required for apoptosis by Par-4 or the SAC domain, and this apoptotic action is not inhibited by Bcl-2 or Bcl-xL overexpression [4, 5].
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