Abstract

TCL-1 and MTCP-1 are members of a novel family of human genes that are involved in T-ell malignancies and lymphoid proliferation and/or survival. These genes code for proteins of about 14 kDa molecular weight, that share 41% identical amino acid residues. Human TCL-1 and MTCP-1 and mouse TCL-1 have been expressed in E. coli and purified in milligram quantities for structural analysis. The crystal structure of MTCP-1 has been determined at 2.0 A resolution. The structure is a unique 8-stranded beta barrel with one short helix. The structure of TCL- 1 is very similar with a root mean square deviation of 1.7 angstrom on all common Calpha atoms. The structural information is being used for site- directed mutagenesis, and to design peptide analogs of surface regions of the proteins as potential inhibitors of oncogene function. Mutant forms of TCL-1 and MTCP-1 will be expressed, characterized and analyzed structurally in comparison to the wild type protein. Interacting proteins and other potential ligands of TCL-1 and MTCP-1 will be studied by crystallography and biochemical methods. The structures and functions of TCL-1 and MTP-1 proteins will be compared. Inhibitors of TCL-1 and MTCP-1 have potential for treatment for low-grade T-cell lymphomas and leukemias.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA076259-01A2
Application #
6232739
Study Section
Special Emphasis Panel (ZCA1-GRB-O (M1))
Project Start
1999-07-27
Project End
2004-04-30
Budget Start
Budget End
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Thomas Jefferson University
Department
Type
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107

  Publications

Thompson, Lorraine H; Whiston, Roy A; Rakhimov, Yerzhan et al. (2010) A LIF/Nanog axis is revealed in T lymphocytes that lack MARCH-7, a RINGv E3 ligase that regulates the LIF-receptor. Cell Cycle 9:4213-21
Almanza, Gonzalo; Fernandez, Antonio; Volinia, Stefano et al. (2010) Selected microRNAs define cell fate determination of murine central memory CD8 T cells. PLoS One 5:e11243
Garzon, Ramiro; Liu, Shujun; Fabbri, Muller et al. (2009) MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 113:6411-8
Ghosh, Asish K; Shanafelt, Tait D; Cimmino, Amelia et al. (2009) Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells. Blood 113:5568-74
Pufnock, Jeff S; Rothstein, Jay L (2009) Oncoprotein signaling mediates tumor-specific inflammation and enhances tumor progression. J Immunol 182:5498-506
Croce, Carlo M (2009) Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10:704-14
Volinia, Stefano; Mascellani, Nicoletta; Marchesini, Jlenia et al. (2008) Genome wide identification of recessive cancer genes by combinatorial mutation analysis. PLoS One 3:e3380
Garzon, Ramiro; Garofalo, Michela; Martelli, Maria Paola et al. (2008) Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci U S A 105:3945-50
Garzon, Ramiro; Volinia, Stefano; Liu, Chang-Gong et al. (2008) MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood 111:3183-9
Tili, Esmerina; Michaille, Jean-Jacques; Cimino, Amelia et al. (2007) Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179:5082-9

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