Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.3.1.21 (
CPT
)
4,580
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The Hodgkin-Reed-Sternberg (HRS) malignant cells in Hodgkin's lymphoma (HL) originate from germinal center B lymphocytes that did not undergo apoptosis. Protein Kinase C (PKC), a family of serine/threonine kinases, plays a crucial role in signal transduction modulating cell growth, differentiation and apoptosis. Here, we report the expression of PKC isoforms in two HL-derived cell lines, L428 and KMH2 and their correlation with drug resistance to
CPT
and doxorubicin. Among the PKC isoforms examined, only PKCeta and PKCbetaII were preferentially expressed in the drug resistant L428 cells. We have shown correlation between the response to apoptosis of L428 and KMH2 cells and PKCeta expression in these cell lines. In order to directly demonstrate a role for PKCeta in apoptosis, its expression was knocked-down by siRNA in the resistant L428 cells. Downregulation of PKCeta rendered L428 cells more sensitive to doxorubicin and
CPT
. Furthermore, PKCeta knocked-down cells showed increased
PARP-1
cleavage, cytochrome c release and caspase 7 activation. It appears that PKCeta functions as an anti-apoptotic protein in HL-derived cell lines, and as we show here that it is also expressed in HRS of HL biopsies, it may have therapeutic relevance in HL. Thus, PKCeta could provide a new target aimed to reduce resistance to anti-cancer treatments of HL and other cancer patients.
...
PMID:PKCeta expression contributes to the resistance of Hodgkin's lymphoma cell lines to apoptosis. 1778 31
Poly(ADP-ribose) polymerase-1 (
PARP-1
) is a nuclear enzyme activated by binding to DNA breaks, which causes
PARP-1
automodification.
PARP-1
activation is required for regulating various cellular processes, including DNA repair and cell death induction.
PARP-1
involved in these regulations is localized in the nucleoplasm, but approximately 40% of
PARP-1
can be found in the nucleolus. Previously, we have reported that nucleolar
PARP-1
is delocalized to the nucleoplasm in cells exposed to DNA-damaging agents. However, the functional roles of this delocalization in cellular response to DNA damage is not well understood, since this approach simultaneously induces the delocalization of
PARP-1
and its automodification. We therefore devised an approach for separating these processes. Unmodified
PARP-1
was first delocalized from the nucleolus using camptothecin. Then,
PARP-1
was activated by exposure of cells to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). In contrast to treatment with MNNG alone, delocalization of
PARP-1
by
CPT
, prior to its activation by MNNG, induced extensive automodification of
PARP-1
. DNA repair activity and consumption of intracellular NAD(+) were not affected by this activation. On the other hand, activation led to an increased formation of apoptotic cells, and this effect was suppressed by inhibition of
PARP-1
activity. These results suggest that delocalization of
PARP-1
from the nucleolus to the nucleoplasm sensitizes cells to DNA damage-induced apoptosis. As it has been suggested that the nucleolus has a role in stress sensing, nucleolar
PARP-1
could participate in a process involved in nucleolus-mediated stress sensing.
...
PMID:Delocalization of nucleolar poly(ADP-ribose) polymerase-1 to the nucleoplasm and its novel link to cellular sensitivity to DNA damage. 1914 73
