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J. Biol. Chem., Vol. 277, Issue 40, 37718-37731, October 4, 2002
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From the The role of Bcl-2 in photodynamic
therapy (PDT) is controversial, and some photosensitizers have been
shown to induce Bcl-2 degradation with loss of its protective function.
Hypericin is a naturally occurring photosensitizer with promising
properties for the PDT of cancer. Here we show that, in HeLa cells,
photoactivated hypericin does not cause Bcl-2 degradation but induces
Bcl-2 phosphorylation in a dose- and time-dependent manner.
Bcl-2 phosphorylation is induced by sublethal PDT doses;
increasing the photodynamic stress promptly leads to apoptosis, during
which Bcl-2 is neither phosphorylated nor degraded. Bcl-2
phosphorylation involves mitochondrial Bcl-2 and correlates with the
kinetics of a G2/M cell cycle arrest, preceding
apoptosis. The co-localization of hypericin with
Phosphorylation of Bcl-2 in G2/M Phase-arrested Cells
following Photodynamic Therapy with Hypericin Involves a
CDK1-mediated Signal and Delays the Onset of Apoptosis*
,,,,,
, and**
Division of Biochemistry, Faculty of
Medicine and Laboratory for Pharmaceutical Biology and
Phytopharmacology, Faculty of Pharmacy, Catholic University of Leuven,
B-3000 Leuven and the § Laboratory of Virology and
Immunology, University of Liege, B-4000 Liege, Belgium
-tubulin and
the aberrant mitotic spindles observed following sublethal PDT doses
suggest that photodamage to the microtubule network provokes the
G2/M phase arrest. PDT-induced Bcl-2 phosphorylation is not
altered by either the overexpression or inhibition of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun
NH2-terminal protein kinase 1 (JNK1) nor by inhibiting the
extracellular signal-regulated kinases (ERKs) or protein kinase C. By
contrast, Bcl-2 phosphorylation is selectively suppressed by the
cyclin-dependent protein kinase (CDK)-inhibitor
roscovitine, completely blocked by the protein synthesis inhibitor
cycloheximide and enhanced by the overexpression of CDK1, suggesting a
role for this pathway. However, in an in vitro kinase
assay, active CDK1/cyclin B1 complex failed to phosphorylate immunoprecipitated Bcl-2, suggesting that this protein kinase may not
directly modify Bcl-2. Mutation of serine-70 to alanine in Bcl-2
abolishes PDT-induced phosphorylation and restores the caspase-3
activation to the same levels of the vector-transfected cells,
indicating that Bcl-2 phosphorylation may be a signal to delay
apoptosis in G2/M phase-arrested cells.
*
This work was supported in part by the Interuniversitaire
Attractiepolen of the Federal Belgian Government and by the
Geconcerteerde Onderzoeksacties (Catholic University of Leuven, Leuven,
Belgium).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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