A balance between proliferation and apoptosis is crucial for cellular homeostasis, and its disruption leading to enhance cellular proliferation and uncontrolled growth are hallmarks of cancer. Loss-of-function mutations that lead to an imbalance in this equilibrium thus represent potential mechanisms of carcinogenesis and cancer progression. Retinoic acid (RA) is an important signaling molecule, which is used as an anti-tumoral agent due to its ability to decrease the growth rate of several cells. However, little is known about the molecular mechanisms underlying the anti-proliferative effects of retinoids. We have identified a novel RA-target gene, Stra 13, which is a basic helix-loop-helix (bHLH) transcription factor. RA, at the transcriptional level, with an immediate early kinetics that coincides with growth arrest, suggesting that it may be a direct target gene that mediates the anti-proliferative effects of RA, up regulating Stra 13 expression. Consistent with this hypothesis, we have recently demonstrated that overexpression of Stra 13 in cells results in growth suppression. To investigate the role of Stra13 in vivo, we have used a loss-of-function (gene-disruption) approach and generated Stra 13-null mice. Preliminary data from mice lacking Stra13 strongly support the hypothesis that it is a key critical regulator of cellular growth of distinct cell types, and that its inactivation promotes carcinogenesis. Thus Stra13 null mice provide an excellent system to dissect the molecular mechanisms underlying its function in regulation of cellular proliferation and growth arrest in vivo. Using cells derived from Stra 13-deficient mice, we wilt investigate various signaling pathways whose alteration could lead to enhanced proliferation of Stra13-/- cells. In addition, we will investigate the role of Stra13 in carcinogenesis, and determine the mechanism of its regulation by RA. Our long-term goal is to gain an insight into the underlying mechanisms by which RA exerts its effects on growth control, with the belief that these results would help extend the therapeutic use of retinoids, and improve our understanding of cancers that arise due to impaired retinoid signaling.
| Liu, Jian-Jun; Chung, Teng-Kai; Li, Jiali et al. (2010) Sharp-1 modulates the cellular response to DNA damage. FEBS Lett 584:619-24 |
