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Cloning and Functional Characterization of Novel R25 Variants of High Mobility Group A1 (HMGA1)
Author(s) -
Deng J. Amy,
Sumter Takita Felder
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.894.1
Subject(s) - transcription factor , biology , dna binding protein , gene , microbiology and biotechnology , cancer research , genetics
In addition to their roles in transcription, proliferation, and viral integration, evidence implicates HMGA1 proteins as mediators of oncogenic transformation. Enforced expression of HMGA1 leads to transformation in vitro and in vivo , potentially explaining the worsened outcomes in patients expressing the proteins. Although several targets of HMGA1 have been identified, the exact pathway is not well understood. The proteins are covalently modified at arginine 25 (R25) and activate transcription of kit ligand (kitL) oncogene in several cancers. To understand the contributions of R25 to HMGA1's oncogenic potential, we generated R25 variants, R25A and R25K, and compared their affinities for kitL to that for HMGA1. The affinity of HMGA1 R25A for kitL was 47% lower than that for the wild type protein suggesting that the arginine residue plays an important role in the DNA binding properties of the protein. The R25K variant also had a 37% lower affinity for kitL . These findings suggest that electrostatic interactions are not required for HMGA1's interactions with putative target genes. Studies are currently underway to correlate DNA binding affinity with oncogenic potential. Understanding the mechanisms of HMGA1‐associated cancers will not only contribute to efforts aimed at preempting cancer during early stages of progression. This research is supported by NIH P20RR04006 and 1R15CA137520‐01 and NSF MCB0542242.