Title | Akt regulation and lung cancer: a novel role and mechanism of action for the tumor suppressor Par-4. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Diaz-Meco MT, Moscat J |
Journal | Cell Cycle |
Volume | 7 |
Issue | 18 |
Pagination | 2817-20 |
Date Published | 2008 Sep 15 |
ISSN | 1551-4005 |
Keywords | Animals, Apoptosis Regulatory Proteins, Humans, Lung Neoplasms, Mice, Mice, Knockout, NF-kappa B, Protein Kinase C, Protein Kinase C-epsilon, Proto-Oncogene Proteins c-akt |
Abstract | The balance between oncogenic and tumor-suppressive signals is central to the control of tumor initiation and progression. Our laboratory identified Par-4, a gene previously discovered in a screen for genes upregulated in cells undergoing apoptosis, as a critical negative regulator of the aPKCs. Par-4 inhibits cell survival and tumorigenesis in vitro, and its genetic inactivation in mice leads to reduced lifespan, enhanced benign tumor development, and low-frequency carcinogenesis. We recently showed that the loss of Par-4 dramatically enhances Ras-induced lung carcinoma formation in vivo, and that, whereas Par-4 is highly expressed in normal lung, it is reduced in a significant proportion of human non-small cell lung carcinomas, strongly suggesting that Par-4 is a relevant tumor suppressor in lung cancer. From a mechanistic point of view, these results unveiled an unexpected and important role of Par-4 as a negative regulator of Akt. We have demonstrated in cell culture, in vivo, and in biochemical experiments that Akt regulation by Par-4 is mediated by PKC zeta, establishing a new paradigm for Akt regulation and demonstrating in vivo that PKC zeta is a physiologically relevant partner of Par-4. |
DOI | 10.4161/cc.7.18.6735 |
Alternate Journal | Cell Cycle |
PubMed ID | 18769154 |
Grant List | R01-AI072581 / AI / NIAID NIH HHS / United States |
Related Faculty:
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.