Genomic mechanisms of p210BCR-ABL signaling: Induction of heat shock protein 70 through the GATA response element confers resistance to paclitaxel-induced apoptosis

Sutapa Ray, Ying Lu, Scott H. Kaufmann, W. Clay Gustafson, Judith E. Karp, Istvan Boldogh, Alan P. Fields, Allan R. Brasier

Research output: Contribution to journalArticle

Abstract

Chronic myelogenous leukemia (CML) results from a t(9,22) translocation, producing the p210BCR-ABL oncoprotein, a tyrosine kinase that causes transformation and chemotherapy resistance. To further understand mechanisms mediating chemotherapy resistance, we identified 556 differentially regulated genes in HL-60 cells stably expressing p210BCR-ABL versus those expressing an empty vector using cDNA macro- and oligonucleotide microarrays. These BCR-ABL-regulated gene products play diverse roles in cellular function including apoptosis, cell cycle regulation, intracellular signaling, transcription, and cellular adhesion. In particular, we identified up-regulation of the inducible form of heat shock protein 70 (Hsp70), and further explored the mechanism for its up-regulation. In HL-60/BCR-ABL and K562 cells (expressing p210BCR-ABL), abundant cytoplasmic Hsp70 expression was detected by immunoblot analysis. Moreover, cells isolated from bone marrow aspirates of patients in different stages of CML (chronic, aggressive, and blast crisis) express Hsp70. Expression of p210BCR-ABL in BCR-ABL negative cells induced transcription of the proximal Hsp70 promoter. Mutational analysis mapped the major p210BCR-ABL responsive element to a high affinity 5′(A/T)GATA(A/G)-3′ "GATA" response element (GATA-RE) that binds GATA-1 in CML cells. The GATA-RE was sufficient to confer p210 BCR-ABL- and p185BCR-ABL-mediated trans-activation to an inert promoter. Short interfering RNA mediated "knockdown" of Hsp70 expression in K562 cells induced marked sensitivity to paclitaxel-induced apoptosis. Together these findings indicate that BCR-ABL confers chemotherapeutic resistance through intracellular signaling to the GATA-RE element found in the promoter region of the anti-apoptotic Hsp70 protein. We suggest that down-regulation of the GATA-Hsp70 pathway may be useful in the treatment of chemotherapy-resistant CML.

Original languageEnglish (US)
Pages (from-to)35604-35615
Number of pages12
JournalJournal of Biological Chemistry
Volume279
Issue number34
DOIs
StatePublished - Aug 20 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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