396
Cell Nucleus Biogenesis, Structure and Function
location might have important implica-
tions for the regulation of gene expression.
A-type lamins bind the retinoblastoma pro-
tein and other transcriptional repressors
and may play important roles in reg-
ulating gene expression through spatial
organization.
Other experiments support the fascinat-
ing possibility that nuclear lamins might
be involved in the processes of DNA and
RNA synthesis. The experimental evidence
involves the introduction into cells – by
microinjection – of bacterially expressed
lamin proteins that have amino-terminal
deletions. The microinjected proteins are
engineered so that they interact with the
endogenous proteins to disrupt stable Fla-
ment formation. It has been reported that
when the lamin Flaments are disrupted in
this way, DNA synthesis and RNA poly-
merase II-dependent RNA synthesis are
also disrupted. One explanation for this is
that lamin Flaments or perhaps smaller
local aggregates of the lamin proteins play
some structural role within the active cen-
tersofDNAandRNAsynthesis.
3.2.4
Lamin-associated Proteins
Many proteins are known to interact with
the lamins to influence lamin function.
These might be classiFed into two broad
groups. Integral proteins of the inner
nuclear membrane are the Frst group
and include various isoforms of lamin-
associated protein 2 (LAP2), LAP1, lamin
B receptor (LBR), emerin, oteFn, MAN1,
Nurim,
nesprin,
RING
Fnger-binding
protein, A-kinase anchoring protein 149,
and p19 (an isoquinoline-binding protein
that is also found in the endoplasmic
reticulum). The second group contains
proteins that associate with the lamins
but are not membrane components. This
group
includes
germ
cell-less
(GCL),
young arrest (YA), PP1 phosphatase and
the transcription factor Oct1.
The nuclear lamina is known to play
a role in chromatin organization and the
lamins can be shown to bind DNA ele-
ments called
nuclear matrix
and scaffold
attachment regions (S/MARs)
in vitro
.
The LAP2 isoforms LAP2
α
and LAP2
β
bind to chromatin. Chromatin binding in-
volves two motifs on the LAP proteins,
a chromatin binding domain and a LEM
domain. The LEM domain is a region of
about 40 amino acids that is also found
in emerin, oteFn and MAN1. The LEM
domain interacts with other chromatin-
associated proteins such as BA± – and
might then influence chromatin architec-
ture and function.
3.2.5
Lamin Mutants
Knockout mice for the lamin A/C gene
has been developed to study lamin func-
tion. Null mice appear normal at birth,
but soon after develop severe growth de-
fects. At about one month after birth the
null mice display reduced mobility and
a stiff walking posture. No mice survive
beyond two months. ±rom histological
examination, it is clear that the affected
mice have skeletal and cardiac muscle
wasting and reduced white fat. ±ibrob-
lasts from the lamin-A knockout mice
show abnormal nuclear blebs, which ap-
pear to result from a dramatically reduced
amount of lamin proteins. The lamin-
associated proteins LAP2 and NUP153 (a
nuclear pore complex protein) are also
signiFcantly reduced. An abnormal dis-
tribution of emerin is also seen, together
with some uncharacteristic features of het-
erochromatin organization. These features
of knockout mice are reminiscent of symp-
toms seen in human patients with Emery
Dreifus muscular dystrophy (EDMD). In-
deed, mutations in
LMNA
have recently
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