Dan Liebermann, PhD

A central theme of my studies has been elucidating the molecular mechanisms of terminal differentiation associated with growth arrest and apoptosis in normal development and genetic lesions which alter these processes and contribute to oncogenesis.

We have made major contributions in the area of normal hematopoietic cell development and leukemogenesis as well as other types of malignancies notably breast cancer. We were the discoverers of the so called myeloid differentiation (MyD) primary response genes, which play an important role in terminal differentiation of hematopoietic cells, including growth arrest, programmed cell death, and function of the cells in innate immunity and inflammation. This includes discovery of several novel genes such as the Gadd45 family of stress response genes and the inflammation innate immunity signal transduction MyD88 gene (see entries in Wikipedia). We have made also pivotal observations, in collaboration with Dr. Barbara Hoffman’s at the Fels, regarding the role c-myc c-myb and E2F play in regulating normal cell development and in blocking terminal differentiation in oncogenic setting. Our recent discoveries indicate that certain MyD genes including Egr-1 and Gadd45 genes are potent tumor suppressor that can abrogate myc, myb and E2F driven oncogenesis.

Current research interests include:

• Identifying molecular targets of Myc/Myb/E2F in blocking terminal differentiation, using cDNA arrays and proteomics approaches.
• Deciphering molecular mechanisms of abrogation of Myc/Myb/E2F oncogenesis by MyD tumor suppression function notably Egr-1 & Gadd45.

We have shown that Gadd45 genes are stress sensors implicated in stress signaling in response to physiological or environmental stressors, which results in cell cycle arrest, DNA repair, cell survival and senescence, or apoptosis. Gadd45 stress sensors functions is mediated via a complex interplay of physical interactions with other cellular proteins that are implicated in cell cycle regulation and the response of cells to stress. These include PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases.

Thus in the context of Gadd45 genes. and by taking advantage of Gadd45 knockout mice we have generated current research is aimed at:

• Understanding Gadd45 role in modulating cellular responses to stress
• Understanding Gadd45 role in hematopoietic stress; notably, modulation of terminal differentiation and the stem cell compartment.
• Exploring Gadd45 role as sensors of oncogenic stress; notably in leukemias and breast cancer.
• Deciphering the role of MyD88 and Gadd45 in innate immunity.
• Investigating role of Gadd45 in the pregnancy related syndrome pre-eclampsia, In collaboration with Dr. Gieffman.
• Interrogating the role of Gadd45 in the response of pre-implantation embryos to stress, n collaboration with Dr. Keith Latham.

Dissecting differentiation and stress induced signaling pathways that induce MyD gene expression; notably Gadd45.