REVIEW ARTICLE
It is all about resolution
Meeting report based upon presentations at the 10th International
Global BioMillennium 2006 symposium on molecular cell biology
(Tbilisi, Georgia)
Hermona Soreq
1
and Alik Honigman
2
1 Department of Biological Chemistry, The Hebrew University of Jerusalem, Israel
2 Department of Virology, The Hebrew University of Jerusalem, Israel
Introduction
Improved resolution in time and space is the hallmark
of studies in diverse subfields of the life sciences,
including epigenetics, structural biology, and electron
tomography. Combined with dynamic imaging of
immune cells and with data management of cDNA
microarrays, such studies yield reliable synchronization
of cell cycle events, with one goal being the develop-
ment of specific microRNA and protein signatures of
particular tumor cell types, and another being to fol-
low the dynamics of neurite growth in the live brains
of mice.
Meeting report
From birth to death of gene products
Until recently, epigenetic mechanisms have been
equated with the inheritance of chromosomal hetero-
chromatin. Evidence that transcriptionally active
states of chromatin can also be epigenetically main-
tained was presented by A. Francis Stewart
(Dresden). Silencing methylations are epigenetically

forces stability.
Three post-transcriptional regulation mechanisms
were presented. Alternative splicing facilitates large pro-
teomic complexity with a limited number of genes, as
was discussed by Javier F. Caceres (Edinburgh, UK).
The trans-acting factors involved include both serine-
arginine (SR) and heterogeneous nuclear ribonucleo-
protein (hnRNP) A ⁄ B proteins, with antagonisti c
activities influencing different modes of alternative spli-
cing in vivo, affecting tissue-specific or developmental
regulation of gene expression. Certain SR and hnRNP
proteins shuttle continuously between the nucleus and
the cytoplasm. Interestingly, hnRNP A1 binds to and is
necessary for the processing of a cluster of intronic
microRNAs suggested to act as a human oncogene.
Nonsense-mediated mRNA decay selectively degrades
mRNAs harboring premature termination codons. In
humans, nonsense-mediated mRNA is linked to
splicing, but in Drosophila and also in Caenorhabditis
elegans, it occurs independently of introns. A polarity
effect reduces nonsense-mediated mRNA sensitivity to a
region close to the 3¢-end of the mRNA.
As a next step in the study of the regulation of
gene expression, Ada Yonath (Rehovot, Israel)
linked ribosomal architecture with antibiotic action.
In all known ribosome structures, an internal symmet-
rical region connects all functional features. The sym-
metry relates the RNA backbone to nucleotide
orientation, but shows no sequence homology. This
demonstrates the superiority of function over

complementary to telomeric DNA. Engineering of
fusion proteins of telomere-binding proteins with yel-
low fluorescent protein and time-lapse imaging were
used to follow the dynamic behavior of telomeres,
which were shown to interact dynamically with nuclear
bodies.
Matthias Gunzer (Braunschweig, Germany) studies
cell motility and migration of immune cells, which
changes considerably when classical liquid cell culture
systems are exchanged for more physiologic environ-
ments. Mimicking the features of true extracellular
tissue can be achieved by embedding the cells in hydra-
ted gels of type 1 collagen, or in undisturbed tissues of
living animals.
Itamar Simon (Jerusalem, Isreal) described a gen-
ome-wide analysis of the human cell cycle in primary
cells. Combining microarray expression data with pre-
cise measurements of the culture synchrony at each
time point enables deconvolution of the temporal
expression signal, yielding coherent, single cell-based
expression patterns. Microarray and complementary
fluorescence-activated cell sorting experiments were
used to test a number of arrest methods for normal
fibroblast cells. Combination of the findings with exist-
ing cancer cell cycle data highlights three groups of
genes ) those that cycle in both cancer and normal
cells; those that cycle only in normal cells; and those
that cycle only in cancer cells ) providing new insights
into the transformation process.
Continuous exchange of macromolecules between

Adi Kimchi (Rehovot, Israel) reported on mole-
cular networks involved in programmed cell death.
She identified gene products, named DAPs (death -
associated proteins), that differ substantially in their
biochemical properties and intracellular localization.
DAP-kinases (DAPk), Ca
2+
⁄ calmodulin-regulated
and Ser ⁄Thr kinases, activate signaling pathways that
lead to cell death through membrane blebbing and
autophagic cell death. Two closely related kinases,
ZIPk and DRP-1, mediate trans-phosphorylation and
subsequent functional activation of ZIPk. DAP5 is a
translation initiation factor that directs internal ribo-
some entry site (IRES)-dependent translation under
stress conditions when translation dependent on
5¢ methyl-protected guanosine, designated ‘cap’, is
compromised. RNA interference technology serves to
knock down various components of the network
singly or in combination, and validate these conclu-
sions. The linking theme in this session highlighted
the need to combine various methodologies in the
search for regulatory events.
Approaching tumorigenesis
The challenge of cross-platform analysis of cancer
microarray data was presented by Roland Eils (Heidel-
berg), who uses median rank scores and quantile dis-
cretization to derive numerically comparable measures
of gene expression from different platforms. Applied
to six publicly available cancer microarray gene expres-

dynamics. During invasive single-cell migration, the
cleavage of individual fiber belts occurs at regions of
focal pressure, such as fiber insertions at branching
pseudopods or nuclear compression zones. These open
small degradation tracks, and continuously expanding
tubes then become filled with cells and mobile cell
masses. Pericellular proteolysis is hence a prerequisite
for expansive tumor growth, collective invasion and
large-scale tissue reshaping. In contrast, single-cell dis-
semination associated with subtle extracellular matrix
remodelling is mechanistically independent of protease
function and may be rescued by nonproteolytic escape
strategies. In this session as well, the complexity of
processes and the need for high-resolution strategies
were evident.
Addressing the brain frontiers
Adi Mizrahi (Jerusalem, Israel) reported the use of
two-photon microscopy for studying how neuronal
dendrites form in adult-born neurons that continuously
develop into the olfactory bulb. Lentivirus green fluor-
escent protein-labeled neurons were used to directly
follow dendritic development in vivo. Within a single
day, neuronal morphology changed dramatically, with
both formation and retraction of whole dendritic trees.
After 10 days, most of the neurons were still migra-
ting. After 45 days, most granule neurons had comple-
ted migration and showed elaborate, complex dendritic
trees. The dynamics of neuronal development in the
intact mammalian brain are hence amenable to further
study.

anxiety-induced changes in cholinergic neurotransmis-
sion that modulate motor control over movement,
working memory, and brain-to-body communication
through the neuron–immune system interface, modify-
ing blood cell composition and platelet production.
Importantly, the acetylcholinesterase ACHE gene
encodes not one protein, but a combinatorial series of
proteins with indistinguishable enzymatic activity but
with variant N-termini and C-termini, due to alternat-
ive promoter usage and 3¢-alternative splicing. These
show distinct nonhydrolytic properties, interact with
variant-specific protein partners, and induce inverse
signaling cascades. Specifically, causal involvement of
both butyrylcholinesterase and acetylcholinesterase in
the progression of Alzheimer’s and Parkinson’s dis-
eases anticipates future therapeutic needs for drugs
targeting specific cholinesterases or the corresponding
RNA transcripts.
Last, but not least, in this session was Leszek Kacz-
marek (Warsaw, Poland), who discussed extracellular
proteolysis in neuronal plasticity, learning and mem-
ory. C-Fos and its functional form, the AP-1 transcrip-
tion factor, emerged in his studies as the best correlate
of learning processes, especially of the behavioral
information. Matrix metalloproteinases (MMPs) are
pivotal for tissue remodeling in the rodent hippocam-
pus, where both matrix metalloproteinase protein-9
(MMP-9) protein and its transcript are associated with
a subset of dendritic spines bearing asymmetric, excita-
tory synapses. Furthermore, functional inactivation of