E. Premkumar Reddy, PhD

• 1993
  Scientific Achievement Award
  

• 1993
  Laura H. Carnell Professor of Medicine
  

Research Interests

Our laboratory is interested in the study of genes that control cell homeostasis and how these controls are dysregulated during the neoplastic process.  We use a combination of biochemistry, molecular biology and synthetic organic chemistry approaches and in close collaboration with the clinical community develop and test small molecule anti-cancer compounds.


We are interested in studying basic biological processes, such as development of the organism through the study of oncogenes such as the myb gene family and cell-cycle regulatory genes such as Cdk4.  We have generated a collection of transgenic and gene knock-out animal models for study of the myb gene family.  Through our studies of the myb gene family, we have begun to understand its role in hematopoietic stem cell development and maintenance and their role in the development of mammary tissue.  We also study the G1 cyclin-dependent kinase, CDK4.  We have developed a nullizygous CDK4 mouse, which displays a phenotype that mimics Type I diabetes, and a CDK4 knock-in mouse that expresses the CDK4R24C protein.  We are using both models to study the role of Cdk4 in the development of cancer.


We also study mechanisms of mitogen activated protein (MAP) kinase signaling through scaffolding proteins belonging to the JIP/JSAP/JLP family.  In 2002, we reported the identification of a MAP kinase scaffolding proteins, JLP, which binds to and coordinately regulates the activities of MEKK3, MKK4, p38MAPK, JNK, Max, c-myc, the kinesin light chain, the stathmin-like protein SCG10, the alpha subumit of the heterotrimeric G protein G13, and the E3 ubiquitin ligase, CHIP.  We are currently undertaking a number of projects aimed at understanding the role of JLP in cell growth and differentiation.


Our basic biology efforts are coordinated with a translational research program to develop and test small molecule anti-cancer therapeutics.  Our chemical biology group has designed and produced a library of nearly 10,000 unique small molecules from approximately 120 individual chemical backbones, or “chemotypes.”  This chemical library has been screened for cytotoxic activity toward cancer cells, while leaving non-malignant tissue intact.  Several of these compounds exhibit kinase inhibitory activities while others seem to inhibit the function of heat shock proteins.  At the present time, we are studying at least 10 such molecules, all with differing mechanisms of action.  Some of these compounds have demonstrated dramatic activity in clinical trials and one of these molecules, ON01910 has been found to have a profound clinical activity in MDS (Myelodysplastic Syndrome) patients.   In combination therapy with Oxaliplatin and Gemcytabine, ON01910 has also been found to have excellent activity in pancreatic and ovarian cancer patients.  Several other kinase inhibitors developed in our laboratory that inhibit Plk2, BCR-ABL, PI3K-a, CK2 have shown pre-clinical activity in cultured cells lines and in animal tumor xenograft models and are being processed for Phase I clinical trials.

The Reddy Laboratory

Reddy EP, Dunn CY, Aaronson SA. Different lymphoid cell targets for transformation by replication competent Moloney and Rauscher leukemia viruses. . Cell 1980; 19: 663-669.

Reddy EP, Reynolds RK, Santos E, Barabcid M. A point mutation is responsible for the activation of T24 human bladder carcinoma oncogene.. Nature 1982; 300: 149-152.

Toscani A, Mattus RV, Simpkins H, Litvin J, Orth J, Hatton KS, Reddy EP. Arrest of spermatogenesis and defective breast development in mice lacking A-myb. Nature 1997; 386: 713-717.

Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP, Barbacid M. Loss of CDK-4 expression causes infertility and insulin deficient diabetes while its activation results in pancreatic islet hyperplasia. Nature . Nature Genetics 1997; 22: 44-52.

Lieu YK, Kumar A, Pajerowski AG, Rogers TJ, Reddy EP. Requirement of c-myb in T cell development and in mature T cell function. Proc Natl Acad Sci U S A 2004; 101: 14853-15858.

Lieu YK, Reddy EP. Conditional c-myb knockout in adult hematopoietic stem cells leads to loss of self-renewal due to impaired proliferation and accelerated differentiation.. Proc Natl Acad Sci U S A 2009; 106: 21689-21694.

Xu H, Dhanasekaran DN, Lee CM, Reddy EP. Regulation of neurite outgrowth by interactions between the scaffolding protein, JNK-associated leucine zipper protein, and neuronal growth-associated protein superior cervical ganglia clone 10. Journal of Biological Chemistry 2010; 285: 3548-3553.

Reddy HK, Mettus RV, Rane SG, Graña X, Litvin J, Reddy EP. Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis.. Cancer Research 2005; 65: 10174-10178.

Reddy HK, Graña X, Dhanasekaran DN, Litvin JJ, Reddy EP. Requirement of Cdk4 for v-Ha-ras–Induced Breast Tumorigenesis and Activation of the v-ras–Induced Senescence Program by the R24C Mutation. . Genes & Cancer 2010; 1: 69-80.

Reddy MV, Mallireddigari MR, Cosenza SC, Pallela VR, Iqbal NM, Robell KA, Kang AD, Reddy EP. Design, synthesis, and biological evaluation of (e)-styrylbenzylsulfones as novel anticancer agents. . Journal of Medicinal Chemistry 2008; 51: 86-100.