Bcr-Abl Regulates Protein Kinase Cι (PKCι) Transcription via an Elk1 Site in the PKCι Promoter

W. Clay Gustafson, Sutapa Ray, Lee Jamieson, E. Aubrey Thompson, Allan R. Brasier, Alan P. Fields

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

The protein kinase C (PKC) family of serine/threonine kinases plays an important role in numerous cancer signaling pathways, including those downstream of the bcr-abl oncogene. We demonstrated previously that atypical PKCι is required for Bcr-Abl-mediated resistance of human K562 chronic myelogenous leukemia (CML) cells to Taxol-induced apoptosis. Here, we report that the pattern of PKC isozyme expression characteristic of CML cells is regulated by Bcr-Abl. When Bcr-Abl was expressed in Bcr-Abl-negative HL-60 promyelocytic leukemia cells, expression of the PKCβI, PKCβII, and PKCι genes was induced, whereas expression of the PKCι gene was reduced to levels similar to those found in CML cells. Given the importance of PKCι in Bcr-Abl-mediated transformation, we characterized the mechanism by which Bcr-Abl regulates PKCι expression. A 1200-bp PKCι promoter construct isolated from genomic DNA was highly active in Bcr-Abl-positive K562 cells and was activated when Bcr-Abl-negative cells were transfected with Bcr-Abl. Bcr-Abl-mediated induction of the PKCι promoter was dependent upon MEK1/2 activity, but not phosphatidylinositol 3-kinase or p38 MAPK activity. Mutational analysis of the PKCι promoter revealed a region between 97 and 114 bp upstream of the transcriptional start site that is responsible for Bcr-Abl-mediated regulation. Mutation of a consensus Elkl-binding site within this region abolished Bcr-Abl-mediated regulation. We conclude that Bcr-Abl regulates PKCι expression through the MEK-dependent activation of an Elk1 element within the proximal PKCι promoter. Our results indicate that Bcr-Abl-mediated transformation involves transcriptional activation of the PKCι gene, which in turn is required for Bcr-Abl-mediated chemoresistance.

Original languageEnglish (US)
Pages (from-to)9400-9408
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number10
DOIs
StatePublished - Mar 5 2004

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Transcription
Protein Kinase C
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Genes
Chemical activation
abl Genes
Phosphatidylinositol 3-Kinase
K562 Cells
Protein-Serine-Threonine Kinases
Mitogen-Activated Protein Kinase Kinases
p38 Mitogen-Activated Protein Kinases
Paclitaxel
Transcriptional Activation
Isoenzymes
Leukemia
Binding Sites
Apoptosis

ASJC Scopus subject areas

  • Biochemistry

Cite this

Bcr-Abl Regulates Protein Kinase Cι (PKCι) Transcription via an Elk1 Site in the PKCι Promoter. / Gustafson, W. Clay; Ray, Sutapa; Jamieson, Lee; Thompson, E. Aubrey; Brasier, Allan R.; Fields, Alan P.

In: Journal of Biological Chemistry, Vol. 279, No. 10, 05.03.2004, p. 9400-9408.

Research output: Contribution to journalArticle

Gustafson, W. Clay ; Ray, Sutapa ; Jamieson, Lee ; Thompson, E. Aubrey ; Brasier, Allan R. ; Fields, Alan P. / Bcr-Abl Regulates Protein Kinase Cι (PKCι) Transcription via an Elk1 Site in the PKCι Promoter. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 10. pp. 9400-9408.
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AU - Gustafson, W. Clay

AU - Ray, Sutapa

AU - Jamieson, Lee

AU - Thompson, E. Aubrey

AU - Brasier, Allan R.

AU - Fields, Alan P.

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N2 - The protein kinase C (PKC) family of serine/threonine kinases plays an important role in numerous cancer signaling pathways, including those downstream of the bcr-abl oncogene. We demonstrated previously that atypical PKCι is required for Bcr-Abl-mediated resistance of human K562 chronic myelogenous leukemia (CML) cells to Taxol-induced apoptosis. Here, we report that the pattern of PKC isozyme expression characteristic of CML cells is regulated by Bcr-Abl. When Bcr-Abl was expressed in Bcr-Abl-negative HL-60 promyelocytic leukemia cells, expression of the PKCβI, PKCβII, and PKCι genes was induced, whereas expression of the PKCι gene was reduced to levels similar to those found in CML cells. Given the importance of PKCι in Bcr-Abl-mediated transformation, we characterized the mechanism by which Bcr-Abl regulates PKCι expression. A 1200-bp PKCι promoter construct isolated from genomic DNA was highly active in Bcr-Abl-positive K562 cells and was activated when Bcr-Abl-negative cells were transfected with Bcr-Abl. Bcr-Abl-mediated induction of the PKCι promoter was dependent upon MEK1/2 activity, but not phosphatidylinositol 3-kinase or p38 MAPK activity. Mutational analysis of the PKCι promoter revealed a region between 97 and 114 bp upstream of the transcriptional start site that is responsible for Bcr-Abl-mediated regulation. Mutation of a consensus Elkl-binding site within this region abolished Bcr-Abl-mediated regulation. We conclude that Bcr-Abl regulates PKCι expression through the MEK-dependent activation of an Elk1 element within the proximal PKCι promoter. Our results indicate that Bcr-Abl-mediated transformation involves transcriptional activation of the PKCι gene, which in turn is required for Bcr-Abl-mediated chemoresistance.

AB - The protein kinase C (PKC) family of serine/threonine kinases plays an important role in numerous cancer signaling pathways, including those downstream of the bcr-abl oncogene. We demonstrated previously that atypical PKCι is required for Bcr-Abl-mediated resistance of human K562 chronic myelogenous leukemia (CML) cells to Taxol-induced apoptosis. Here, we report that the pattern of PKC isozyme expression characteristic of CML cells is regulated by Bcr-Abl. When Bcr-Abl was expressed in Bcr-Abl-negative HL-60 promyelocytic leukemia cells, expression of the PKCβI, PKCβII, and PKCι genes was induced, whereas expression of the PKCι gene was reduced to levels similar to those found in CML cells. Given the importance of PKCι in Bcr-Abl-mediated transformation, we characterized the mechanism by which Bcr-Abl regulates PKCι expression. A 1200-bp PKCι promoter construct isolated from genomic DNA was highly active in Bcr-Abl-positive K562 cells and was activated when Bcr-Abl-negative cells were transfected with Bcr-Abl. Bcr-Abl-mediated induction of the PKCι promoter was dependent upon MEK1/2 activity, but not phosphatidylinositol 3-kinase or p38 MAPK activity. Mutational analysis of the PKCι promoter revealed a region between 97 and 114 bp upstream of the transcriptional start site that is responsible for Bcr-Abl-mediated regulation. Mutation of a consensus Elkl-binding site within this region abolished Bcr-Abl-mediated regulation. We conclude that Bcr-Abl regulates PKCι expression through the MEK-dependent activation of an Elk1 element within the proximal PKCι promoter. Our results indicate that Bcr-Abl-mediated transformation involves transcriptional activation of the PKCι gene, which in turn is required for Bcr-Abl-mediated chemoresistance.

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