Abstract

We previously identified and characterized a 66‐68 kDa membrane‐associated, tyrosine phosphorylated protein in murine leukemia L1210 cells as HSC70 which is a methotrexate (MTX) ‐ binding protein. We further characterize the functional role of HSC70 in regulating MTX resistance in L1210 cells. The tyrosine phosphorylation status of the HSC70 in the membrane fraction is different between the parental L1210/0 and cisplatin (CDDP)‐MTX cross resistant L1210/DDP cells. The binding assay with MTX‐agarose beads showed HSC70 in the L1210/DDP cells had less binding ability with MTX compared with L1210/0 cells. In addition, genistein (a tyrosine phosphorylation inhibitor) significantly enhanced the resistance of L1210/0 cells to MTX. In addition, site‐directed mutation studies indicated the importance of tyrosine phosphorylation of HSC70 in regulating its binding to MTX. These studies suggested that tyrosine phosphorylation may contribute to the functions of HSC70 in regulating MTX resistance in L1210 cells.Grant Funding Source: Supported by National Institutes of Health Grant P20 RR16454 and P20 GM103408

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