Many studies have highlighted the pathological involvement of iron accumulation and iron-related oxidative stress (OS) in Alzheimer's disease (AD). Iron was further demonstrated to modulate ...expression of the Alzheimer's amyloid precursor holo-protein (APP) by a mechanism similar to that of regulation of ferritin-L and -H mRNA translation through an iron-responsive element (IRE) in their 5' untranslated regions (UTRs). Here, we discuss two aspects of the link between iron and AD, in relation to the recently discovered IRE in the 5'UTR of APP mRNA. The first is the physiological aspect: a compensatory neuroprotective response of amyloid-beta protein (Abeta) in reducing iron-induced neurotoxicity. Thus, given that Abeta possesses iron chelation sites, it is hypothesized that OS-induced intracellular iron may stimulate APP holo-protein translation (via the APP 5'UTR) and subsequently the generation of its cleavage product, Abeta, as a compensatory response that eventually reduces OS. The second is the pathological aspect: iron chelating compounds target the APP 5'UTR and possess the capacity to reduce APP translation, and subsequently Abeta levels, and thus represent molecules with high potential in the development of drugs for the treatment of AD.
The human GH receptor (hGHR) contains nine intracellular and seven
extracellular cysteines, of which six are linked by disulfide bonds and
one, at position 241 proximal to the membrane, is free. ...Recently, an
alternatively spliced GHR isoform has been isolated; it encodes a
truncated receptor lacking most of the cytoplasmic domain (hGHRtr). In
the present study, we have examined the effect of sulfhydryl group(s)
inactivation on receptor internalization and GH binding-protein (GHBP)
generation from the human (h) and rabbit (rb) full-length GHR, as well
as from hGHRtr and a mutant of the free extracellular cysteine
(hGHRtr-C241A), expressed in Chinese hamster ovary (CHO) cells. In
CHO/rbGHR and CHO/hGHR cells, permeable sulfhydryl-reactive agents,
like N-ethylmaleimide (NEM) and iodacetamide (IA),
inhibited GHR internalization and induced an immediate dose-dependent
loss of cellular GHR, associated with a concomitant marked increase in
released GHBP. In contrast, the membrane impermeable IA derivative
A-484 had no effect on either GHBP release or on GHR internalization.
NEM exposure of CHO cells, expressing hGHRtr, resulted in a
dose-dependent increase in GHBP generation, but only a moderate
decrease in cellular hGHRtr. The importance of the only unpaired
cysteine in these processes was evaluated in CHO/hGHRtr-C241A cells.
hGHRtr-C241A was similar to hGHRtr in its impaired internalization and
enhanced GHBP release by NEM.
Taken together, these data suggest that intracellular sulfhydryl
groups, within membranal endocytic vesicles, that do not belong to the
GHR molecule, are involved in receptor internalization and GHBP
generation. In addition, the present study demonstrates that despite
impaired hGHR internalization/down-regulation, the inducible release of
GHBP was not affected, further suggesting that GHR endocytosis is not a
prerequisite for GHBP generation.
We report here the isolation of a novel cDNA, designated LIS2, that maps to chromosome 2p11.2 by in situ hybridization and demonstrates extremely high sequence similarity to the recently identified ...LIS1 gene involved in Miller-Dieker lissencephaly at 17p13.3. Specific probes for LIS2 revealed a pattern of expression resembling that of LIS1, although LIS2 is less abundant. Surprisingly, LIS2 detected an additional, higher molecular weight transcript in adult skeletal muscle. Isolated YAC clones and P1 clones mapped by in situ hybridization to two loci on chromosome 2,2p11.2 and 2q13-q14. This hybridization was due to the existence of LIS2 pseudogene LIS2P on the long arm of chromosome 2.
We report here the isolation of a novel cDNA, designatedLIS2,that maps to chromosome 2p11.2 byin situhybridization and demonstrates extremely high sequence similarity to the recently ...identifiedLIS1gene involved in Miller–Dieker lissencephaly at 17p13.3. Specific probes forLIS2revealed a pattern of expression resembling that ofLIS1,althoughLIS2is less abundant. Surprisingly,LIS2detected an additional, higher molecular weight transcript in adult skeletal muscle. Isolated YAC clones and P1 clones mapped byin situhybridization to two loci on chromosome 2, 2p11.2 and 2q13–q14. This hybridization was due to the existence ofLIS2pseudogeneLIS2Pon the long arm of chromosome 2.
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