Gregory David, PhD
Stress induced cell cycle exit, chromatin modifiers and cancer
Senescence; Cancer; Chromatin modifiers; Hematopoietic Stem Cells; Transcription.
Bone marrow failure results from the inability of hematopoietic stem cells (HSC) to self-renew and to continuously repopulate the hematopoietic system. Such defects are triggered by exposure to diverse stresses, ranging from exposure to environmental mutagens to administration of anti-cancer chemotherapy. Identifying means to restore the characteristic self-renewal properties of these cells thus represents a priority in the field. It has recently been demonstrated that, in the bone marrow of patients treated with ionizing radiations, high-dose chemotherapy, and patients affected by myelodysplastic syndromes (MDS), HSC undergo a permanent cell cycle exit, called cellular senescence, correlating with their inability to self-renew. However, the molecular bases for HSC’s entry in senescence in these pathological situations remain largely unknown. Using genetically engineered mice and cells, we have recently demonstrated that specific chromatin modifiers, including the histone deacetylase -associated Sin3B protein, are required for cellular senescence triggered by exposure to various stimuli. Therefore, we hypothesize that specific chromatin modifiers activities lie at the nexus of stress and HSC fate decisions in bone marrow failure syndromes. Additionally, we are interested in expanding our initial observations to study the contribution of chromatin pathways in stem cells from different organs, including skin and the GI track, throughout the malignant transformation process.
Grandinetti KB, Jelinic P, DiMauro T, Pellegrino J, Rodríguez RF, Finnerty PM, Ruoff R, Bardeesy N, Logan SK and David G. 2009. Sin3B expression is required for cellular senescence and is upregulated upon oncogenic stress. Cancer Research; 69(16): 6430-7. PMID:19654306
DiMauro T and David G. 2010. Ras induced senescence and its physiological relevance in tumor suppression. Current Cancer Drug Targets. Dec;10(8):869-76. Invited Review. PMID: 20718709
van Oevelen C, Bowman C, Pellegrino J, Asp P, Cheng J, Parisi F, Kluger Y, Chu A, Blais A, David G*, and Dynlacht BD*. 2010. The mammalian Sin3 proteins are required for muscle development and sarcomere specification. Mol Cell Biol. 30(24):5686-97. PMID: 20956564
Jelinic P, Pellegrino J, and David G. 2011. A novel mammalian complex containing Sin3B mitigates histone acetylation and RNAPII progression within transcribed loci. Mol Cell Biol. 31(1):54-62. PMID: 21041482
Xie T, Graveline R, Kumar G, Zhang Y, Krishnan A, David G* and Radhakrishnan I*. 2012. Structural basis for molecular interactions involving MRG domains: implications in chromatin biology. Structure. 20(1):151-60. PMID: 22244764
Kumar SK, Chang W, Xie T, Patel A, Zhang Y, Wang GG, David G, Radhakrishnan I. 2012. Sequence Requirements for Combinatorial Recognition of Histone H3 by the MRG15 and Pf1 Subunits of the Rpd3S/Sin3S Corepressor Complex. J Mol Biol. 422(4):519-31. PMID: 22728643
David G. 2012. Regulation of Oncogene-induced cell cycle exit and Senescence by Chromatin modifiers. Cancer Biol. Ther. 13(11): 992-1000. PMID: 22825329
Pellegrino J, Castrillon DH, David G. 2012. Chromatin associated Sin3A is essential for male germ cell lineage in the mouse. Dev Biol. 15;369(2):349-55. PMID: 22820070
Yang W, Wang X, David G , Dorsey JF . 2012. Dissecting the complex regulation of Mad4 in glioblastoma multiforme cells. Cancer Biol. Ther. 13(13):1339-48. PMID: 22895069
Lee E, Madar A, David G, Garabedian M, Dasgupta R, Logan S. 2013. Inhibition of androgen receptor and bCatenin Activity in prostate cancer cells. Proc Natl Acad Sci. USA. 110(39):15710-5. PMID: 24019458
Rielland M, Cantor D, Graveline R, Mara L, Hadju C, Miller G, David G. 2014. Senescence-associated Sin3B promotes inflammation and pancreatic cancer progression. Journal of Clinical Investigation. In Press.