Role of p53-regulated sestrin genes in lung cancer
Abstracts
Initial Award Abstract |
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Tobacco smoking produces numbers of Reactive Oxygen Species (ROS). ROS are highly reactive chemicals formed from oxygen by cellular metabolism, which might play an important role in lung carcinogenesis inducing genetic changes and accelerating tumor growth and metastasis. Normal cells have an effective way to protect themselves against ROS, but these mechanisms might be lost in cancer cells. Accordingly, lung cancers often demonstrate increased levels of ROS production and accumulation, which might be advantageous for tumor growth. Nevertheless the genetic changes responsible for the increase in accumulation ROS in lung cancer cells and the roles of ROS in cancer progression are still unclear. We hypothesize that cellular proteins involved in protection against ROS-induced damage might play an important role in suppression of lung cancer.
We have shown previously that two related genes Hi95 and PA26, which are members of the sestrin gene family, regulate ROS accumulation, protect cells and their DNA against oxidative damage and regulate cell growth and viability. These genes are often deregulated in lung cancers and their inactivation accelerates the growth of model tumors in mice. The activity of these genes might therefore be important for suppression of lung cancer development, but the role of the Hi95 and PA26 sestrin genes in lung cancer has never been studied. We presume that inactivation of these genes may increase the risk of lung cancer and inactivation of these genes can play an important role in lung tumorigenesis.
The mouse has emerged as a primary model animal for studying human lung carcinogenesis due to similarities between human and mouse lung cancers and abnormalities causing the disease in both species. Transgenic mouse models are currently being used to study controlled genetic changes in lung and other types of cancer. The methodology, called “conditional knock-out”, applies the inactivation of certain gene or genes only in special organ, such as the lung. I will generate mice that lack expression of either or both sestrin genes in the lung cells and examine the effect of these genetic alterations on the development of lung cancer in normal conditions and after carcinogens exposure. The specific inactivation of these genes in lung cells will offer for the first time the ability to study the regulation of ROS accumulation and determine the how oxidative stress in lung may affect an incidence and progression of lung cancer. Also we will study how the inactivation of the sestrin genes may cooperate with the other genetic lesion such as inactivation of tumor suppressor genes in cancer progression. We will analyze the survival and possible abnormalities in these mice. We will study genetic and biochemical changes which may appear in epithelial cells, lung fibroblasts and cancer cells of these mice. |
