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Dan Liebermann., PhD
Professor, Fels Institute for Cancer Research and Molecular Biology
Telephone: 215-707- 6903
Department of Biochemistry
Fels Institute for Cancer Research and Molecular Biology
Education and career training:
B.Sc./prMD - Tel Aviv University, Israel
PhD Molecular Genetics - Weizmann Institute, Israel
Postdoctoral Fellow - Stanford University School of Medicine
Assistant Professor - University of Pennsylvania School of Medicine
Professor - Temple University School of Medicine, Fels Institute and Department of Biochemistry
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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 (see schematic diagram below).
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 (see schematic diagram below).
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.
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Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)
24104471. Hoffman B, Liebermann DA, Gadd45 in modulation of solid tumors and leukemia. Adv Exp Med Biol 793:(21-33)2013
22802593. Leach PT, Poplawski SG, Kenney JW, Hoffman B, Liebermann DA, Abel T, Gould TJ, Gadd45b knockout mice exhibit selective deficits in hippocampus-dependent long-term memory. Learn Mem 19:8(319-24)2012 Jul 16
22718299. Xiong Y, Liebermann DA, Holtzman EJ, Jeronis S, Hoffman B, Geifman-Holtzman O, Preeclampsia-associated stresses activate Gadd45a signaling and sFlt-1 in placental explants. J Cell Physiol 228:2(362-70)2013 Feb
22307729. Salerno DM, Tront JS, Hoffman B, Liebermann DA, Gadd45a and Gadd45b modulate innate immune functions of granulocytes and macrophages by differential regulation of p38 and JNK signaling. J Cell Physiol 227:11(3613-20)2012 Nov
22150313. Liebermann DA, Tront JS, Sha X, Mukherjee K, Mohamed-Hadley A, Hoffman B, Gadd45 stress sensors in malignancy and leukemia. Crit Rev Oncog 16:1-2(129-40)2011
21098706. Tront JS, Huang Y, Fornace AJ Jr, Hoffman B, Liebermann DA, Gadd45a functions as a promoter or suppressor of breast cancer dependent on the oncogenic stress. Cancer Res 70:23(9671-81)2010 Dec 1
20642319. Geifman-Holtzman O, Xiong Y, Holtzman EJ, Hoffman B, Gaughan J, Liebermann DA, Increased placental telomerase mRNA in hypertensive disorders of pregnancy. Hypertens Pregnancy 29:4(434-45)2010
19834918. Zumbrun SD, Hoffman B, Liebermann DA, Distinct mechanisms are utilized to induce stress sensor gadd45b by different stress stimuli. J Cell Biochem 108:5(1220-31)2009 Dec 1
19652693. Cretu A, Sha X, Tront J, Hoffman B, Liebermann DA, Stress sensor Gadd45 genes as therapeutic targets in cancer. Cancer Ther 7:A(268-276)2009
19452502. Xiong Y, Liebermann DA, Tront JS, Holtzman EJ, Huang Y, Hoffman B, Geifman-Holtzman O, Gadd45a stress signaling regulates sFlt-1 expression in preeclampsia. J Cell Physiol 220:3(632-9)2009 Sep
19229137. Engel N, Tront JS, Erinle T, Nguyen N, Latham KE, Sapienza C, Hoffman B, Liebermann DA, Conserved DNA methylation in Gadd45a(-/-) mice. Epigenetics 4:2(98-9)2009 Feb 16
18955973. Hoffman B, Liebermann DA, Apoptotic signaling by c-MYC. Oncogene 27:50(6462-72)2008 Oct 27
18789159. Liebermann DA, Hoffman B, Gadd45 in stress signaling. J Mol Signal 3:(15)2008 Sep 12
18780287. Hoffman B, Liebermann DA, Gadd45 modulation of intrinsic and extrinsic stress responses in myeloid cells. J Cell Physiol 218:1(26-31)2009 Jan
18650844. Gibbs JD, Liebermann DA, Hoffman B, Leukemia suppressor function of Egr-1 is dependent on transforming oncogene. Leukemia 22:10(1909-16)2008 Oct
18247372. D'Angelo S, Liebermann D, Hoffman B, The c-myc apoptotic response is not intrinsic to blocking terminal myeloid differentiation. J Cell Physiol 216:1(120-7)2008 Jul
17686638. Hoffman B, Liebermann DA, Role of gadd45 in myeloid cells in response to hematopoietic stress. Blood Cells Mol Dis 39:3(344-7)2007 Nov-Dec
17659913. Liebermann DA, Hoffman B, Gadd45 in the response of hematopoietic cells to genotoxic stress. Blood Cells Mol Dis 39:3(329-35)2007 Nov-Dec
17599039. Gibbs JD, Liebermann DA, Hoffman B, Egr-1 abrogates the E2F-1 block in terminal myeloid differentiation and suppresses leukemia. Oncogene 27:1(98-106)2008 Jan 3
17495532. Gibbs JD, Liebermann DA, Hoffman B, Terminal myeloid differentiation is uncoupled from cell cycle arrest. Cell Cycle 6:10(1205-9)2007 May 15
17264673. Liebermann DA, Hoffman B, Vesely D, p53 induced growth arrest versus apoptosis and its modulation by survival cytokines. Cell Cycle 6:2(166-70)2007 Jan 15
17099722. Vesely DL, Hoffman B, Liebermann DA, Phosphatidylinositol 3-kinase/Akt signaling mediates interleukin-6 protection against p53-induced apoptosis in M1 myeloid leukemic cells. Oncogene 26:21(3041-50)2007 May 10
16951155. Tront JS, Hoffman B, Liebermann DA, Gadd45a suppresses Ras-driven mammary tumorigenesis by activation of c-Jun NH2-terminal kinase and p38 stress signaling resulting in apoptosis and senescence. Cancer Res 66:17(8448-54)2006 Sep 1
16732331. Gupta SK, Gupta M, Hoffman B, Liebermann DA, Hematopoietic cells from gadd45a-deficient and gadd45b-deficient mice exhibit impaired stress responses to acute stimulation with cytokines, myeloablation and inflammation. Oncogene 25:40(5537-46)2006 Sep 7
16636063. Gupta M, Gupta SK, Hoffman B, Liebermann DA, Gadd45a and Gadd45b protect hematopoietic cells from UV-induced apoptosis via distinct signaling pathways, including p38 activation and JNK inhibition. J Biol Chem 281:26(17552-8)2006 Jun 30
16170381. Gupta M, Gupta SK, Balliet AG, Hollander MC, Fornace AJ, Hoffman B, Liebermann DA, Hematopoietic cells from Gadd45a- and Gadd45b-deficient mice are sensitized to genotoxic-stress-induced apoptosis. Oncogene 24:48(7170-9)2005 Nov 3
15840692. Shafarenko M, Liebermann DA, Hoffman B, Egr-1 abrogates the block imparted by c-Myc on terminal M1 myeloid differentiation. Blood 106:3(871-8)2005 Aug 1
14982872. Shafarenko M, Amanullah A, Gregory B, Liebermann DA, Hoffman B, Fos modulates myeloid cell survival and differentiation and partially abrogates the c-Myc block in terminal myeloid differentiation. Blood 103:11(4259-67)2004 Jun 1
12972029. Liebermann DA, Hoffman B, Myeloid differentiation (MyD) primary response genes in hematopoiesis. Blood Cells Mol Dis 31:2(213-28)2003 Sep-Oct
12932304. Balliet AG, Hollander MC, Fornace AJ Jr, Hoffman B, Liebermann DA, Comparative analysis of the genetic structure and chromosomal mapping of the murine Gadd45g/CR6 gene. DNA Cell Biol 22:7(457-68)2003 Jul
12917673. Amanullah A, Azam N, Balliet A, Hollander C, Hoffman B, Fornace A, Liebermann D, Cell signalling: cell survival and a Gadd45-factor deficiency. Nature 424:6950(741; discussion 742)2003 Aug 14
12351382. Rane SG, Mangan JK, Amanullah A, Wong BC, Vora RK, Liebermann DA, Hoffman B, Graņa X, Reddy EP, Activation of the Jak3 pathway is associated with granulocytic differentiation of myeloid precursor cells. Blood 100:8(2753-62)2002 Oct 15
12124778. Vairapandi M, Balliet AG, Hoffman B, Liebermann DA, GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. J Cell Physiol 192:3(327-38)2002 Sep
12070012. Sjin RM, Krishnaraju K, Hoffman B, Liebermann DA, Transcriptional regulation of myeloid differentiation primary response (MyD) genes during myeloid differentiation is mediated by nuclear factor Y. Blood 100:1(80-8)2002 Jul 1
12032779. Hoffman B, Amanullah A, Shafarenko M, Liebermann DA, The proto-oncogene c-myc in hematopoietic development and leukemogenesis. Oncogene 21:21(3414-21)2002 May 13
12032777. Liebermann DA, Hoffman B, Myeloid differentiation (MyD) primary response genes in hematopoiesis. Oncogene 21:21(3391-402)2002 May 13
11960329. Liebermann DA, Hoffman B, Myeloid differentiation (MyD)/growth arrest DNA damage (GADD) genes in tumor suppression, immunity and inflammation. Leukemia 16:4(527-41)2002 Apr
11896589. Amanullah A, Liebermann DA, Hoffman B, Deregulated c-Myc prematurely recruits both Type I and II CD95/Fas apoptotic pathways associated with terminal myeloid differentiation. Oncogene 21:10(1600-10)2002 Feb 28
11403721. Balliet AG, Hatton KS, Hoffman B, Liebermann DA, Comparative analysis of the genetic structure and chromosomal location of the murine MyD118 (Gadd45beta) gene. DNA Cell Biol 20:4(239-47)2001 Apr
11251170. Zhang W, Hoffman B, Liebermann DA, Ectopic expression of MyD118/Gadd45/CR6 (Gadd45beta/alpha/gamma) sensitizes neoplastic cells to genotoxic stress-induced apoptosis. Int J Oncol 18:4(749-57)2001 Apr
11222373. Krishnaraju K, Hoffman B, Liebermann DA, Early growth response gene 1 stimulates development of hematopoietic progenitor cells along the macrophage lineage at the expense of the granulocyte and erythroid lineages. Blood 97:5(1298-305)2001 Mar 1
11022036. Azam N, Vairapandi M, Zhang W, Hoffman B, Liebermann DA, Interaction of CR6 (GADD45gamma ) with proliferating cell nuclear antigen impedes negative growth control. J Biol Chem 276:4(2766-74)2001 Jan 26
10967552. Vairapandi M, Liebermann DA, Hoffman B, Duker NJ, Human DNA-demethylating activity: a glycosylase associated with RNA and PCNA. J Cell Biochem 79:2(249-60)2000 Aug 2
10887108. Amanullah A, Hoffman B, Liebermann DA, Deregulated E2F-1 blocks terminal differentiation and loss of leukemogenicity of M1 myeloblastic leukemia cells without abrogating induction of p15(INK4B) and p16(INK4A). Blood 96:2(475-82)2000 Jul 15
10871848. Amanullah A, Liebermann DA, Hoffman B, p53-independent apoptosis associated with c-Myc-mediated block in myeloid cell differentiation. Oncogene 19:26(2967-77)2000 Jun 15
10828887. Bernardi R, Liebermann DA, Hoffman B, Cdc25A stability is controlled by the ubiquitin-proteasome pathway during cell cycle progression and terminal differentiation. Oncogene 19:20(2447-54)2000 May 11
10828065. Vairapandi M, Azam N, Balliet AG, Hoffman B, Liebermann DA, Characterization of MyD118, Gadd45, and proliferating cell nuclear antigen (PCNA) interacting domains. PCNA impedes MyD118 AND Gadd45-mediated negative growth control. J Biol Chem 275:22(16810-9)2000 Jun 2
10497240. Sjin RM, Lord KA, Abdollahi A, Hoffman B, Liebermann DA, Interleukin-6 and leukemia inhibitory factor induction of JunB is regulated by distinct cell type-specific cis-acting elements. J Biol Chem 274:40(28697-707)1999 Oct 1
10490824. Zhang W, Bae I, Krishnaraju K, Azam N, Fan W, Smith K, Hoffman B, Liebermann DA, CR6: A third member in the MyD118 and Gadd45 gene family which functions in negative growth control. Oncogene 18:35(4899-907)1999 Sep 2
9916997. Hoffman B, Liebermann DA, The proto-oncogene c-myc and apoptosis. Oncogene 17:25(3351-7)1998 Dec 24
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