Michael Khodadoust
e-mail address: mkhodado@umich.edu

Mentor: David Markovitz, MD

Research Description

DEK is an abundant mammalian nuclear protein that has been identified as an autoantigen in several autoimmune diseases. Although DEK is abundantly expressed in most tissues, its cellular function remains unknown. The link between DEK and autoimmunity has been best established in juvenile rheumatoid arthritis (JRA). Anti-DEK autoantibodies can be detected in up to 77% of patients with the pauci-articular form of JRA. Notably, 98% of JRA patients suffering from uveitis, one of the most feared complications of JRA, produce anti-DEK antibodies. In addition to its association with autoimmune diseases, DEK appears to be overexpressed in numerous malignancies, including hepatocellular carcinoma, melanoma, glioblastoma, and bladder cancer.

The majority of DEK appears to be bound to DNA and may serve to help modulate transcription and maintain chromatin structure. However, we have noted that under certain conditions, DEK can be released from chromatin in some cells. When glioblastoma cells are treated with an inhibitor of histone deacetylases, DEK appears to accumulate in sub-nuclear structures rich in RNA processing factors called interchromatin granule clusters. The presence of DEK in these clusters supports the ongoing notion of a role for DEK in RNA processing. Additionally, we have found that differentiation and activation of human peripheral blood monocytes results in the translocation of DEK into the cytoplasm and its subsequent extracellular secretion. Furthermore, this secreted form of DEK appears to act as a potent chemoattractant for neutrophils and certain T cell populations.

The implication of DEK in these quite disparate processes suggests the presence of multiple mechanisms regulating the activity of DEK. One likely form of regulation is post-translational molecular modification. Indeed, DEK's affinity for target DNA sequences is reduced by phosphorylation and, as we have recently demonstrated, also by acetylation. My work involves further elucidating the role of DEK in RNA processing and immune processes by investigating the localization and function of phosphorylated and acetylated DEK. Utilizing pharmacologic treatments and mutant forms of DEK, I hope to better understand the function of DEK in both normal and pathologic states.

Publications

Journal Articles:

Mor-Vaknin N, Punturieri A, Sitwala K, Faulkner N, Legendre M, Khodadoust MS, Kappes F, Ruth JH, Koch A, Glass D, Petruzzelli L, Adams BS, Markovitz DM. The DEK nuclear autoantigen is a secreted chemotactic factor. Mol Cell Biol. 2006 Dec;26(24):9484-96.

Cleary J, Sitwala KV, Khodadoust MS, Kwok RP, Mor-Vaknin N, Cebrat M, Cole PA, Markovitz DM. p300/CBP-associated factor drives DEK into interchromatin granule clusters. J Biol Chem. 2005 Sep 9;280(36):31760-7.

Meeting Abstracts:

Khodadoust, M., Balajee, S. A., Marr, K. A. Aspergillus pathogenicity correlates with intracellular resistance to macrophage killing: Results using a novel flow-cytometric assay. Abstracts of the General Meeting of the American Society for Microbiology  101 : 376 2001.

Hu GY , Khodadoust M , Konopleva M , Huang ZW , Andreeff M . Induction of apoptosis in lymphoid cell lines and primary CLL by HA14-1, a cell permeable organic small molecule that binds to the BH1 to BH3 surface pocket of Bcl-2 protein. Blood  98 (11): 3491 Part 1 NOV 16 2001.

Khodadoust M , Konopleva M , Leysath C , Frankel SR , Giles FJ , Andreeff M . Bcl-2 antisense oligodeoxynucleotide (Genasense) enhances gemtuzumab ozogamicin (Mylotarg)-induced cytotoxicity in acute myeloid leukemia. Blood  98 (11): 429 Part 1 NOV 16 2001.

Andreeff M , Konopleva M , Leysath C , Khodadoust M , Huang Z . Induction of apoptosis in primary human leukemia cells by HA14-1, a cell-permeable organic compound identified by protein structure-based computer screening that binds the BH1 to BH3 surface pocket of Bcl-2. Clin Cancer Res  7 (11): 344 Suppl. S NOV 2001.