1: Mech Dev. 2005 Nov 5; [Epub ahead of print] 

XBP1 forms a regulatory loop with BMP-4 and suppresses mesodermal and neural
differentiation in Xenopus embryos.

Cao Y, Knochel S, Oswald F, Donow C, Zhao H, Knochel W.

Abteilung Biochemie, Universitat Ulm, Albert-Einstein-Allee 11, D-89081 Ulm,
Germany.

The active form of the Xenopus X-box binding protein 1 (xXBP1) partially
synergizes and partially antagonizes with BMP-4 signaling. xXBP1 overexpression
inhibits mesoderm differentiation and formation of neural tissues. A functional
knockdown promotes differentiation of lateral and dorsal mesoderm but not of
ventral mesoderm and of neuroectoderm. We show that the active form of xXBP1 in
gastrula and early neurula stage embryos is generated by removal of exon 4 and
not by an endoribonuclease activity in the endoplasmic reticulum. The N-terminal
region of xXBP1 which contains the basic leucine-zipper also contains a nuclear
localization signal and both, the N-terminal as well as the C-terminal regions
are required for xXBP1 function. The effects of xXBP1 are in part correlated to
a regulatory loop between xXBP1 and BMP-4. xXBP1 and BMP-4 stimulate mutually
the transcription of each other, but xXBP1 inhibits the BMP-4 target gene,
Xvent-2. Both, in vitro and in vivo assays demonstrate that xXBP1 interacts with
BMP-4 and Xvent-2B promoters. GST-pulldown assays reveal that xXBP1 can interact
with c-Jun, the transcriptional co-activator p300 and with the BMP-4 responsive
Smad1. On the other hand, xXBP1 also binds to the inhibitory Smads, Smad6 and
Smad7, that can act as transcriptional co-repressors. Based on these data, we
conclude that xXBP1 might function as an inhibitor of mesodermal and neural
tissue formation by acting either as transcriptional activator or as repressor.
This dual activity depends upon binding of co-factors being involved in the
formation of distinct transcription complexes.

PMID: 16278078 [PubMed - as supplied by publisher]


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2: J Biol Chem. 2003 May 23;278(21):19367-77. Epub 2003 Feb 21. 

Parkinsonian mimetics induce aspects of unfolded protein response in death of
dopaminergic neurons.

Holtz WA, O'Malley KL.

Anatomy and Neurobiology Department, Washington University School of Medicine,
St. Louis, Missouri 63110, USA.

Genes associated with Parkinson's disease (PD) have suggested a role for
ubiquitin-proteasome dysfunction and aberrant protein degradation in this
disorder. Inasmuch as oxidative stress has also been implicated in PD, the
present study examined transcriptional changes mediated by the
Parkinsonism-inducing neurotoxins 6-hydroxydopamine (6-OHDA) and
1-methyl-4-phenylpyridinium (MPP+) in a dopaminergic cell line. Microarray
analysis of RNA isolated from toxin treated samples revealed that the
stress-induced transcription factor CHOP/Gadd153 was dramatically up-regulated
by both 6-OHDA and MPP+. Treatment with 6-OHDA also induced a large number of
genes involved in endoplasmic reticulum stress and unfolded protein response
(UPR) such as ER chaperones and elements of the ubiquitin-proteasome system.
Reverse transcription-PCR, Western blotting, and immunocytochemical approaches
were used to quantify and temporally order the UPR pathways involved in
neurotoxin-induced cell death. 6-OHDA, but not MPP+, significantly increased
hallmarks of UPR such as BiP, c-Jun, and processed Xbp1 mRNA. Both toxins
increased the phosphorylation of UPR proteins, PERK and eIF2 alpha, but only
6-OHDA increased phosphorylation of c-Jun. Thus, 6-OHDA is capable of triggering
multiple pathways associated with UPR, whereas MPP+ exhibits a more restricted
response. The involvement of UPR in these widely used neurotoxin models supports
the role of ubiquitin-proteasome pathway dysfunction in PD.

PMID: 12598533 [PubMed - indexed for MEDLINE]


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