Activation of protein kinase Cδ by all-trans-retinoic acid

Suman Kambhampati, Yongzhong Li, Amit K. Verma, Antonella Sassano, Beata Majchrzak, Dilip K. Deb, Simrit Parmar, Nick Giafis, Dhananjaya V. Kalvakolanu, Arshad Rahman, Shahab Uddin, Saverio Minucci, Martin S. Tallman, Eleanor N. Fish, Leonidas C. Platanias

Research output: Contribution to journalArticle

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Abstract

All-trans-retinoic acid (RA) is a potent inhibitor of leukemia cell proliferation and induces differentiation of acute promyelocytic leukemia cells in vitro and in vivo. For RA to induce its biological effects in target cells, binding to specific retinoic acid nuclear receptors is required. The resulting complexes bind to RA-responsive elements (RAREs) in the promoters of RA-inducible genes to initiate gene transcription and to generate protein products that mediate the biological effects of RA. In this report, we provide evidence that a member of the protein kinase C (PKC) family of proteins, PKCδ, is activated during RA treatment of the NB-4 and HL-60 acute myeloid leukemia cell lines as well as the MCF-7 breast cancer cell line. Such RA-dependent phosphorylation was also observed in primary acute promyelocytic leukemia cells and resulted in activation of the kinase domain of PKCδ. In studies aimed at understanding the functional relevance of PKCδ in the induction of RA responses, we found that pharmacological inhibition of PKCδ (but not of other PKC isoforms) diminished RA-dependent gene transcription via RAREs. On the other hand, overexpression of a constitutively active form of the kinase strongly enhanced RA-dependent gene transcription via RAREs. Gel shift assays and chromatin immunoprecipitation studies demonstrated that PKCδ associated with retinoic acid receptor-α and was present in an RA-inducible protein complex that bound to RAREs. Pharmacological inhibition of PKCδ activity abrogated the induction of cell differentiation and growth inhibition of NB-4 blast cells, demonstrating that its function is required for such effects. Altogether, our data provide strong evidence that PKCδ is activated in an RA-dependent manner and plays a critical role in the generation of the biological effects of RA in malignant cells.

Original languageEnglish (US)
Pages (from-to)32544-32551
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number35
DOIs
StatePublished - Aug 29 2003
Externally publishedYes

Fingerprint

Tretinoin
Protein Kinase C
Chemical activation
Transcription
Genes
Acute Promyelocytic Leukemia
Retinoic Acid Receptors
Cells
Phosphotransferases
Pharmacology
Cohort Effect
Cell Line
Proteins
Chromatin Immunoprecipitation
Phosphorylation
Myeloid Cells
Cytoplasmic and Nuclear Receptors
Cell proliferation
Acute Myeloid Leukemia
Cell Differentiation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Kambhampati, S., Li, Y., Verma, A. K., Sassano, A., Majchrzak, B., Deb, D. K., ... Platanias, L. C. (2003). Activation of protein kinase Cδ by all-trans-retinoic acid. Journal of Biological Chemistry, 278(35), 32544-32551. https://doi.org/10.1074/jbc.M301523200

Activation of protein kinase Cδ by all-trans-retinoic acid. / Kambhampati, Suman; Li, Yongzhong; Verma, Amit K.; Sassano, Antonella; Majchrzak, Beata; Deb, Dilip K.; Parmar, Simrit; Giafis, Nick; Kalvakolanu, Dhananjaya V.; Rahman, Arshad; Uddin, Shahab; Minucci, Saverio; Tallman, Martin S.; Fish, Eleanor N.; Platanias, Leonidas C.

In: Journal of Biological Chemistry, Vol. 278, No. 35, 29.08.2003, p. 32544-32551.

Research output: Contribution to journalArticle

Kambhampati, S, Li, Y, Verma, AK, Sassano, A, Majchrzak, B, Deb, DK, Parmar, S, Giafis, N, Kalvakolanu, DV, Rahman, A, Uddin, S, Minucci, S, Tallman, MS, Fish, EN & Platanias, LC 2003, 'Activation of protein kinase Cδ by all-trans-retinoic acid', Journal of Biological Chemistry, vol. 278, no. 35, pp. 32544-32551. https://doi.org/10.1074/jbc.M301523200
Kambhampati S, Li Y, Verma AK, Sassano A, Majchrzak B, Deb DK et al. Activation of protein kinase Cδ by all-trans-retinoic acid. Journal of Biological Chemistry. 2003 Aug 29;278(35):32544-32551. https://doi.org/10.1074/jbc.M301523200
Kambhampati, Suman ; Li, Yongzhong ; Verma, Amit K. ; Sassano, Antonella ; Majchrzak, Beata ; Deb, Dilip K. ; Parmar, Simrit ; Giafis, Nick ; Kalvakolanu, Dhananjaya V. ; Rahman, Arshad ; Uddin, Shahab ; Minucci, Saverio ; Tallman, Martin S. ; Fish, Eleanor N. ; Platanias, Leonidas C. / Activation of protein kinase Cδ by all-trans-retinoic acid. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 35. pp. 32544-32551.
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abstract = "All-trans-retinoic acid (RA) is a potent inhibitor of leukemia cell proliferation and induces differentiation of acute promyelocytic leukemia cells in vitro and in vivo. For RA to induce its biological effects in target cells, binding to specific retinoic acid nuclear receptors is required. The resulting complexes bind to RA-responsive elements (RAREs) in the promoters of RA-inducible genes to initiate gene transcription and to generate protein products that mediate the biological effects of RA. In this report, we provide evidence that a member of the protein kinase C (PKC) family of proteins, PKCδ, is activated during RA treatment of the NB-4 and HL-60 acute myeloid leukemia cell lines as well as the MCF-7 breast cancer cell line. Such RA-dependent phosphorylation was also observed in primary acute promyelocytic leukemia cells and resulted in activation of the kinase domain of PKCδ. In studies aimed at understanding the functional relevance of PKCδ in the induction of RA responses, we found that pharmacological inhibition of PKCδ (but not of other PKC isoforms) diminished RA-dependent gene transcription via RAREs. On the other hand, overexpression of a constitutively active form of the kinase strongly enhanced RA-dependent gene transcription via RAREs. Gel shift assays and chromatin immunoprecipitation studies demonstrated that PKCδ associated with retinoic acid receptor-α and was present in an RA-inducible protein complex that bound to RAREs. Pharmacological inhibition of PKCδ activity abrogated the induction of cell differentiation and growth inhibition of NB-4 blast cells, demonstrating that its function is required for such effects. Altogether, our data provide strong evidence that PKCδ is activated in an RA-dependent manner and plays a critical role in the generation of the biological effects of RA in malignant cells.",
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AU - Majchrzak, Beata

AU - Deb, Dilip K.

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AU - Giafis, Nick

AU - Kalvakolanu, Dhananjaya V.

AU - Rahman, Arshad

AU - Uddin, Shahab

AU - Minucci, Saverio

AU - Tallman, Martin S.

AU - Fish, Eleanor N.

AU - Platanias, Leonidas C.

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AB - All-trans-retinoic acid (RA) is a potent inhibitor of leukemia cell proliferation and induces differentiation of acute promyelocytic leukemia cells in vitro and in vivo. For RA to induce its biological effects in target cells, binding to specific retinoic acid nuclear receptors is required. The resulting complexes bind to RA-responsive elements (RAREs) in the promoters of RA-inducible genes to initiate gene transcription and to generate protein products that mediate the biological effects of RA. In this report, we provide evidence that a member of the protein kinase C (PKC) family of proteins, PKCδ, is activated during RA treatment of the NB-4 and HL-60 acute myeloid leukemia cell lines as well as the MCF-7 breast cancer cell line. Such RA-dependent phosphorylation was also observed in primary acute promyelocytic leukemia cells and resulted in activation of the kinase domain of PKCδ. In studies aimed at understanding the functional relevance of PKCδ in the induction of RA responses, we found that pharmacological inhibition of PKCδ (but not of other PKC isoforms) diminished RA-dependent gene transcription via RAREs. On the other hand, overexpression of a constitutively active form of the kinase strongly enhanced RA-dependent gene transcription via RAREs. Gel shift assays and chromatin immunoprecipitation studies demonstrated that PKCδ associated with retinoic acid receptor-α and was present in an RA-inducible protein complex that bound to RAREs. Pharmacological inhibition of PKCδ activity abrogated the induction of cell differentiation and growth inhibition of NB-4 blast cells, demonstrating that its function is required for such effects. Altogether, our data provide strong evidence that PKCδ is activated in an RA-dependent manner and plays a critical role in the generation of the biological effects of RA in malignant cells.

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