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The Response of Tumor Cells
to Stress and Chemotherapy
The Role of PKC
Etta Livneh
Faculty of Health Sciences
PKCeta confers protection against
cell death
•
Primarily expressed in epithelial tissues and cells with high turn-over.
Epithelia-the origin for 90% of tumors. Protects from cell death
(Abu-Ghanem
•
et al 2007, Rotem-Dai et al 2009, Karp et al 2007, Raveh-Amit et al 2011, Shahaf et al 2012).
In breast cancer patients-Its upregulation and localization in the cell
membranes and the nuclear envelope predicts response to treatment.
(Karp et al 2012).
•
In NSCLC patients - PKCeta is a novel prognostic marker.
(Krasnitsky et al 2012).
•
Unique intracellular localization: ER/Golgi and cytoplasm. Shuttles between
the cytoplasm and the nucleus and is tethered to the nuclear envelope upon
DNA damage.
(Maissel et al. 2006; Tamarkin et al. 2011).
PKCeta translocates to the NE in
response to DNA Damage
•Only the C1b domain is sufficient
for protection against cell death
•What is the entity that is formed
in the membrane that tethers
PKCeta to the membrane?
•What is the signalling pathway
activated in the membrane?
Role of PKC in authophagy and
senescence
•
PKCeta is involved in cell cycle regulation at G1/S phase
•
PKCeta is an upstream regulator of NFkB
(Fima et al 2001, Fishman et al 1998, Kashiwagi et al 2000, Livneh et al 1996, Livneh and Fishman 1997,
Shtutman et al 2003).
(Raveh-Amit et al 2011)
•
PKCeta induces secretion of IL-6 in fibroblasts
(Fima et al 1999).
•
Premature senescence is enhanced by PKCeta in response to
oxidative stress and DNA damage.
•
The polymorphic variant 374I (associated with cerebral
infarction, Rheumatoid Arthritis (RA), gastric atrophy) more
active as a kinase, is more effective in IL-6 secretion, the
expression of the cell cycle inhibitor p21 and b-Gal staining
supporting the role of PKCeta in senescence.
Cellular Senescence in Hodgkin's
Lymphoma
In collaboration with J. Gopas and D. BenHarroch
PKCeta is expressed in astrocytes in AD
mice model is found near Ab plaques
APP/PS1 - Cortex
PKCη
GFAP
Ab
Merge
In collaboration with A. Monsonego
Novel regulation at the translational level via
upstream open reading frames (uORFs): Role in
response to stress
5’cap
uORF
Main ORF
M. musculus
PKC-γ
R. norvegicus
H. sapiens
PKC-ε
M. musculus
R. norvegicus
H. sapiens
PKC-η
M. musculus
R. norvegicus
H. sapiens variant 1
H. sapiens variant 2
PKC-ξ
H. sapiens variant 3
M. musculus
R. norvegicus
In collaboration with M. Shapira
•Are the peptides
translated?
•Do they have a biological
function?
•Different regulation in
normal and tumor cells.
In CSC?
Looking for collaboration in the
following areas:
1. We have shown a novel mode of regulation of the expression of proteins
via uORFs in the 5'UTR of the mRNA (ongoing collaboration with
Prof. Michal Shapira). As we suggest that the translation of peptides
is involved in this regulation, we are also interested in sensitive
methods for the detection and separation of peptides.
2. In the last years we have focused on the role of PKC in the protection
against cell death. We are interested in collaboration on signaling
pathways involved in apoptosis, authophagy and senescence.
3. We are interested in mice models of breast cancer or glioblastoma to
explore the role of cancer stem cells (CSCs).
4. Design of novel inhibitors for protein kinases (small molecules or
peptides) and high throughput screening for their screening