 |
about | Maps & Directions | contact | admissions | faculty | alumni & development | library | Tech Support Center | dean's office | Policies & Procedures |
 Site Map
|
|
about | Maps & Directions | contact | admissions | faculty | alumni & development | library | Tech Support Center | dean's office | Policies & Procedures |
 |
 |
 |
FAculty directory
E. Premkumar Reddy , PhD
Director, Fels Institute for Cancer Research and Molecular Biology Professor, Fels Institute for Cancer Research and Molecular Biology Professor, Biochemistry Telephone: 215-707-4307 Fax: 215-707-1454 Email: premkumar.reddy@temple.edu
Fels Institute for Cancer Research and Molecular BiologyDepartment of Biochemistry
Dr. Reddy's work is focused on the following five areas: (1) Role of the Myb gene family in development and cancer: The myb gene family consists of three members, named A, B and c-myb, all of which encode nuclear proteins which bind DNA in a sequence-specific manner and function as regulators of transcription. The c-myb and A-myb genes are highly expressed in many tumors tissues. Our lab has generated A-myb null mutant mice and showed that loss of A-myb expression results in a defect in testis development as well as a loss of progesterone-induced proliferative events associated with breast tissue development leading to an absence of lactation. To biologically define the function of c-myb, we have generated conditional knock-out mice, which are currently being used to study the role of this gene in the development of breast, brain and hematopoietic tissues. We are also trying to define the roles c-myb and A-myb in breast cancer using genetic approaches such as knocking-in activating mutations in these genes. Our laboratory also first discovered that the c-myb gene codes for two alternatively mRNAs, which encode for two different proteins, p75-Myb and p89-Myb. Our studies have shown that under conditions of stress, p75-Myb acquires a pro-apoptotic function, while p89-Myb shows anti-apoptotic activity. Recently, we have generated a p89 null mutant mouse model and currently studies are under way to define the function of p89-Myb.
(2) Role of CDK4 in development, cell cycle regulation and cancer: Cdk4 is an important regulator of G1/S cell cycle progression and germline mutations in the 24th codon of this gene (R to C) result in a predisposition of the individuals to melanoma. To study the function of this gene, our group has generated two strains of mice, one that lacks Cdk4 expression (Cdk4 neo/neo) and a second one that expresses an activated form of this enzyme (Cdk4 R24C). Cdk4 null mutant mice were found to be diabetic exhibiting defective pancreatic ß-cell development as well as breast development. In addition, an analysis of compound mice ectopically expressing the Neu and wnt oncogenes in the mammary glands of wild type and CDK4-/- mice showed that CDK4 expression is required for efficient Neu, but dispensable for Wnt-induced tumorigenesis. This data suggests that drugs targeted to inhibit CDK4 activities could be developed to specifically treat certain beast tumors, as CDK4 is not essential for viability. On the other hand, Cdk4(R24C/R24C) mouse embryo fibroblasts (MEFs) display increased Cdk4-kinase activity resulting in hyperphosphorylation of all three members of the Rb-family. These MEFs display decreased doubling times, escape from replicative senescence and exhibit a high degree of susceptibility to oncogene-induced transformation. In addition, Cdk4(R24C/R24C) mice rapidly develop tumors of varying etiology within 8-10 months of their birth. Current studies are aimed at understanding the nature of secondary mutational events that develop during tumor development and the molecular basis for the phenotypes seen in these two sets of mice.
(3) Signal transduction pathways associated with apoptosis and stress: This project focuses on the role three novel genes discovered by us, JLP, AATYK and JAK-3. Our group has identified a novel scaffolding protein, JLP, which acts as a tethering molecule to bring together Myc and Max along with JNK and p38 MAPK, as well as their upstream kinases MKK4 and MEKK3. Our recent studies show that JLP plays a critical role in endodermal and neuronal development through regulation of JNK-mediated signal transduction pathways. Studies are currently under way to dissect the role of this gene in development through the use of conditional knock-out mice.
A second novel gene discovered by us is called AATYK (Apoptosis Associated Tyrosine Kinase), whose expression is dramatically upregulated during apoptotic death of 32Dcl3 cells. Expression of this gene is blocked in transformed myeloid cells which are deficient in undergoing apoptosis. Interestingly, this gene is highly expressed in the neurons of the mammalian brain and loss of this gene (in AATYK-/- mice) leads to embryonic lethality. Our goals are to carry out a detailed biochemical characterization of the AATYK protein to determine the nature of its potential tyrosine kinase activity, its post-translational modification patterns, its interaction with other signaling molecules, its mechanism of action and mechanisms associated with its transcriptional regulation. We are also generating conditional knock-out mice to study its function in brain development.
Investigators in the lab have also isolated a novel JAK kinase, termed JAK3 whose over-expression appears to result in the acceleration of terminal differentiation of myeloid precursor cells. Studies are in progress to delineate this signal transduction cascade and identify and clone the cDNAs of genes induced by this signaling mechanism. Characterization of these cDNAs is likely to provide new insights into the mechanisms associated with myeloid cell differentiation.
(4) Targeted therapies for cancer:. Our group has developed a novel group of compounds for cancer therapy which are selectively toxic to cancer cells but innocuous to non-cancerous cells. Studies show that these compounds block normal cell cycle progression in the G1 phase, where they can survive for prolonged periods of time. In contrast, these compounds block tumor cell growth in the mitotic phase of the cell cycle, resulting in their death due to apoptosis. Currently studies are under way to define the precise mechanisms of action of these compounds. In addition, we have developed a number of potential cancer therapeutic agents that specifically inhibit a select group of tyrosine and serine/threonine kinases, which are going through pre-clinical development. One of these compounds, ON01910, is currently going through Phase I clinical trials for the treatment of cancer. We have also developed three novel Cycloxygenase-2 (COX-2) inhibitors which are very effective in inducing apoptotic death of human tumor cell lines which appears to be associated with their ability to activate the TNF/DR5 pathway. Our group is currently examining the mechanism of action and the chmopreventive and therapeutic effects of these novel COX-2 inhibitors.
|
|
