Signal Transduction Program

The malignant transformation of cells involves alterations in the control of cell cycle progression, the ability of the cells to terminally differentiate and the capacity to undergo programmed cell death (apoptosis) in response to normal cellular cues. Most of these functions are controlled through biochemical signal transducing events that occur following engagement of one or more of a variety of cell surface receptors. The goals of the Signal Transduction program are to define the critical signal transducing pathways involved in normal cellular regulation and the pathways that are altered in transformed cells. The members of the program come from 10 academic departments and are investigating receptors of the Fc family that includes the B- and T-cell receptors, cytokine receptors and tyrosine kinase family receptors and use a variety of approaches to identify and establish the role for individual signaling pathways. Using this basic information, studies are focused on identifying how these cellular controls are altered in transformed cells and assessing the role of various pathways in transformation using both biochemical and genetic approaches. The ultimate goal of the studies of signal transduction is to develop novel therapeutic approaches that are based on targeting normal signaling pathways or pathways that are altered in transformation.

The Signal Transduction Program was established in 1995 to provide an organized entity to bring together investigators that are interested in the general area of signal transduction. The goals of the program include promoting exchange of information to facilitate the development of individual research programs and to provide forums in which ongoing research can be critically evaluated by a wide range of investigators pursuing various aspects of signal transduction. The continual exchange and evaluation of ongoing research also has fostered a wide variety of collaborative studies as illustrated by the publications. The Signal Transduction program consists of Cancer Center Members representing 10 academic departments within St. Jude Children’s Research Hospital.

The central function of the program is to provide a forum for exchange and review of ongoing research as well as to foster the development of intra- and inter-programmatic collaborations. This is accomplished through two types of seminar programs. The first, more formal, seminar series is held every other week on Tuesdays at 9:00 AM. Individuals from the program present their work in a formal, one-hour seminar that is intended to include background information as well as work accomplished. In the case of postdoctoral fellows it is utilized to practice the seminars they will use to interview for faculty positions. Following the presentations there is a question and answer period. In addition, the faculty often convenes to further review the progress that has been made and to make suggestions relative to the presentation, the course of the research and the possibilities for collaborations. The second seminar series is held every week on Thursday at 9:00 AM. This series is much more informal and focuses on notebook type presentations of ongoing research. The background information is generally not provided. Exchanges occur throughout the presentation that normally involves a single individual. This series is intended to focus on the research and to provide a critical forum for evaluating ongoing studies and to provide suggestions for future experiments both in direction and in techniques to address scientific questions. Together the seminar series has brought together investigators and served as the catalyst for many inter- and intra-programmatic collaborations, some of which are indicated below.

Members of the Signal Transduction Program interact with clinical investigators and with individuals of other Cancer Center Programs. Many investigators from the program have participated and still participate on the CPSRMC to provide an opportunity for more basic research investigators to become aware of the institutional clinical activities and to provide them knowledge and experience in the development of clinical protocols. This has been an important source of translational opportunities and collaborations between clinical and basic investigators.  Within the Program, Dr. Mary Ellen Conley is an internationally recognized clinical investigator in genetic immunodeficiencies and has been instrumental in helping to develop gene therapy studies for immunodeficiencies associated with Jak3 mutations that are currently being pursued by Drs. Brian Sorrentino and James Ihle.  Members of the Signal Transduction Program participate in a Gene Therapy for Sickle Cell program project grant. One component of the program is the development of vectors that could be used in approaches to improve drug therapy in cancer treatment. For several years Dr. Ihle was a scientific advisor for Ligand Pharmaceuticals in San Diego which licensed technology for St. Jude involved with the role of Jak kinases in cytokine signaling. This resulted in the development of a small molecule mimic for thrombopoietin, in a collaboration with Glaxo Smith Kline, which has completed phase III trials and will be requested for use to increase platelets in cancer patients undergoing intensive chemotherapy.  Dr. Martine Roussel participates as a project co-leader for Project 5 in the Normal and Neoplastic Growth Regulation in the Brain Tumor Program.  This program project grant is an inter-programmatic collaboration to increase our understanding of normal and neoplastic growth in the developing brain and to identify and test new therapies in pediatric brain tumors. 

The malignant transformation of cells often involves alterations in the control of cell cycle progression, the ability of the cells to terminally differentiate or to undergo apoptosis in response to normal extra-cellular cues. These functions are most frequently controlled through biochemical signal transducing events that occur following the engagement of one or more of a variety of cell surface receptors. The goals of this program are three-fold.

The first goal is to define the critical signal transducing pathways that are used in normal cellular regulation through a variety of receptor systems including cytokine receptors, tyrosine kinase receptors and members of the Fc receptor family that includes both the B- and T-cell antigen receptors. Members of the program are using a variety of approaches to identify novel proteins/enzymes that are involved in signal transduction. This includes the use of microarrays, proteomics approaches, genetic analysis as well as standard biochemical methods. Of particular interest to several of the signal transduction program members are the pathways that contribute to preventing or inducing apoptosis.  The goal of defining pathways has been greatly facilitated by the Cancer Center particularly the support provided by the Bioinformatics & Biotechnology Core. Most investigators in the program derive genetically modified mouse strains to assess the physiological roles of novel pathways and this has been greatly facilitated by the Cancer Center Animal Resource Center and Transgenic/Gene Knockout Cores.

The second goal of the research in this program is to define the events that occur in transformation to alter normal regulation through alteration of signal transduction pathways. Investigators utilize a number of approaches to accomplish this goal including the identification of genes associated with retrovirally induced tumors in mice and the genes associated with chromosomal breakpoints that characterize human hematopoietic malignancies. As the identification of specific components of signal transducing pathways are identified, their role in the sequence of events is determined through the utilization of standard biochemical transformation assays as well as genetic models including gene deletions, insertion of specific gene mutations (knock-in) to mimic those found in human tumors, and transgenic approaches.

The last goal is to begin to utilize this information to develop novel therapeutic approaches that are based on targeting normal signaling pathways or mimicking alterations that occur during transformation. The recruitment of a new Department of Chemical Biology will greatly facilitate the screening of new compounds. One area of particular interest to members of the program is the signal transducing events that can alter the response of cells to chemotherapeutic agents through the suppression of apoptosis. Intervention in these pathways is envisioned to increase the sensitivity of cells to chemotherapy. Moreover, program members have shown that transforming events may inherently put cells at risk of apoptosis and that tumor evolution requires suppression of this sensitivity.  Intervention in the signaling pathways that suppress apoptosis may therefore be sufficient to control tumor growth.

The ability to achieve these scientific goals is dependent upon three factors that represent the essential contributions that the Cancer Center organization provides. First, the Signal Transduction Program provides the critical forum to bring investigators together from across our academic structure to focus on the above goals. The seminar programs are the “frontline” at which ideas are presented, challenged and fine-tuned by a diverse and talented group of investigators exploring a variety of signaling pathways. Secondly, the resources provided through the cores provide the tools that both make possible and facilitate experiments that allow the goals to be achieved in a timely fashion. Of particular note are the resources provided by the Animal Resources Center, the Transgenic/Gene Knockout Facility, Cell Microinjection & Live Cell Imaging, Protein Production and Bioinformatics & Biotechnology.  Lastly, the depth of clinical experience and activity at St. Jude Children’s Research Hospital, found in many of the Cancer Center Programs, continues to challenge our investigators in the Signal Transduction Program to translate basic information into clinical opportunities and provide avenues to accomplish this challenge for our Program activities through inter-programmatic collaborations.

James N. Ihle, PhD, and Martine F. Roussel, PhD, are co-leaders of the program.


Email This Article Email This Article   |   Print Print