Mitochondrial targeting of JNK/SAPK in the phorbol ester response of myeloid leukemia cells
Abstract
Treatment of human U-937 myeloid leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with activation of the stress-activated protein kinase (SAPK) and induction of terminal monocytic differentiation. The present studies demonstrate that TPA targets SAPK to mitochondria by a mechanism dependent on activation of protein kinase C (PKC) beta. Translocation of SAPK to mitochondria in response to TPA is associated with release of cytochrome c, caspase-3 activation and induction of apoptosis. The results show that TPA induces the association of SAPK with the mitochondrial anti-apoptotic Bcl-x(L) protein. Overexpression of Bcl-x(L) attenuated the apoptotic response to TPA treatment. Moreover, expression of Bcl-x(L) mutated at sites of SAPK phosphorylation (Thr-47, -115) was more effective than wild-type Bcl-x(L) in abrogating TPA-induced cytochrome c release and apoptosis. By contrast, expression of Bcl-x(L) had little effect on induction of the monocytic phenotype. These findings indicate that myeloid leukemia cells respond to TPA with targeting of SAPK to mitochondria and that this response contributes to terminal differentiation through the release of cytochrome c and induction of apoptosis.
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Translocation of JNK to mitochondria is essential for cytochrome c release and apoptosis downstream of other stress activators.
“other studies have shown that translocation of JNK to the mitochondria was essential for cytochrome c release and apoptosis downstream of other stress activators (67, 189).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [189]
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References 34 · Cited by 62
- Authors
- Ito, Y., Mishra, N. C., Yoshida, K., Kharbanda, S., Saxena, S., & Kufe, D.
- Affiliations
- Harvard University (US)
- Lovelace Respiratory Research Institute (US)
- Corresponding author
- Kufe, D
- Venue
- Cell Death & Differentiation
- Published
- 2001-07-24
- Volume
- 8
- Issue
- 8
- Pages
- 794-800
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- OpenAlex
- W2330002713
- Cited by
- 62
- References
- 34
- Citations by year
- 2026: 1 · 2021: 1 · 2020: 2 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 3.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy (FC0496AL76406)
- U.S. Department of Health and Human Services
- National Cancer Institute (R01CA042802, CA42802)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- SAPK/JNK, mitochondrial targeting, phorbol ester, phorbol myristate acetate, myeloid leukemia, U937 cells, protein kinase C beta, cytochrome c release, caspase-3 activation, apoptosis, Bcl-xL, c-Jun N-terminal kinase
- MeSH terms
- Carcinogens, Cell Compartmentation, Cell Differentiation, Cytochrome c Group, Fluorescent Antibody Technique, Humans, Isoenzymes, Leukemia, Myeloid, Mitochondria, Monocytes, Protein Kinase C, Tetradecanoylphorbol Acetate, Tumor Cells, Cultured, Immunoblotting, Gene Expression Regulation, Leukemic, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Mitogen-Activated Protein Kinases, Myeloid Progenitor Cells, Mitogen-Activated Protein Kinase 8, bcl-X Protein, Protein Kinase C beta
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