Cancer:
lung
Prostate
J Biol Chem. 2006 Mar 22; [Epub
ahead of print] Oncogene. 2005 Feb 24;24(9):1641-7. J Biol Chem. 2006 Feb 17;281(7):3889-98.
Epub 2005 Dec 14. Cardiovasc Res. 2006 Feb 1;69(2):520-6.
Epub 2005 Dec 1.
Bcl2
suppresses DNA repair by enhancing c-Myc
transcriptional activity.
Jin Z, May WS, Gao
F, Flagg
T, Deng X.
Department of Medicine, University of
Bcl2 and c-Myc are two major oncogenic
proteins that can functionally promote DNA damage, genetic instability and tumorigenesis. However, the mechanism(s) remains
unclear. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) is the most potent carcinogen contained in cigarette smoke that
induces cellular DNA damage. Here we found that Bcl2 potently suppresses
the repair of NNK-induced abasic sites of DNA
lesions in association with increased c-Myc
transcriptional activity. Bcl2's BH4 domain (aa 6-31) was found to bind directly to c-Myc's MBII domain (aa
106-143) and this interaction is required for Bcl2 to enhance c-Myc transcriptional activity and inhibit DNA repair. In
addition to mitochondria, Bcl2 is also expressed in the nucleus where it
co-localizes with c-Myc. Expression of
nuclear-targeted Bcl2 enhances c-Myc
transcriptional activity with suppression of DNA repair but fails to
prolong cell survival. Depletion of c-Myc
expression from cells overexpressing Bcl2
significantly accelerates the repair of NNK-induced DNA damage, indicating
that c-Myc may be essential for Bcl2's effect on
DNA repair. It is known that APE1 plays a crucial role in the repair of abasic sites of DNA lesions. Since overexpression
of Bcl2 results in up-regulation of c-Myc and
down-regulation of APE1, this suggests that APE1 may function as the
downstream target of Bcl2/c-Myc in the DNA repair machinery. Thus, Bcl2, in
addition to its survival function, may also suppress DNA repair in a novel
mechanism involving c-Myc and APE1, which may
lead to an accumulation of DNA damage in living cells, genetic instability
and tumorigenesis.
PMID: 16554306 [PubMed - as supplied by publishe
Redox factor 1 (Ref-1) enhances specific DNA binding of
p53 by promoting p53 tetramerization.
Hanson
S, Kim
E, Deppert W.
Heinrich-Pette-Institute for
Experimental Virology and Immunology at the
Sequence-specific DNA binding is a major activity of the tumor suppressor
p53 and a prerequisite for the transactivating
potential of the protein. p53 interaction with
target DNA is tightly regulated by various mechanisms, including binding of
different components of the transcription machinery, post-translational
modifications, and interactions with other factors that modulate p53 transactivation in a cell context- and
promoter-specific manner. The bi-functional redox
factor 1 (Ref-1/APE1) has been identified as one of the factors, which can
stimulate p53 DNA binding by redox-dependent as
well as redox-independent mechanisms. Whereas
stimulation of p53 DNA binding by the redox
activities of Ref-1 is understood quite well, little is known about
mechanisms that underlie the redox-independent
effects of Ref-1. We report in this study a previously unknown activity of
Ref-1 as a factor promoting tetramerization of
p53. We demonstrate that Ref-1 promotes association of dimers
into tetramers, and de-stacking of higher oligomeric
forms into the tetrameric form in vitro, thereby
enhancing p53 binding to target DNA.
PMID: 15674341 [PubMed - indexed for MEDLINE]
Nucleotide sequence and DNA secondary
structure, as well as replication protein A, modulate the single-stranded abasic endonuclease activity
of APE1.
Fan J, Matsumoto Y,
Wilson DM 3rd.
Laboratory of Molecular Gerontology, NIA, National
Institutes of Health,
A major role of the multifunctional human Ape1 protein is to incise at apurinic/apyrimidinic (AP) sites in DNA via
site-specific endonuclease activity. This
nuclease function has been well characterized on double-stranded (ds) DNA substrates, where the complementary strand
provides a template for subsequent base excision repair events. Recently,
Ape1 was found to incise efficiently at AP sites positioned within the
single-stranded (ss) regions of various
biologically relevant DNA configurations. The studies within indicated that
the ss endonuclease
activity of Ape1 is poorly active on ss AP
site-containing polyadenine or polythymine oligonucleotides,
suggesting a requirement for some form of DNA secondary structure for
efficient cleavage. Computational, footprinting,
and biochemical analyses indicated that the nature of the secondary
structure and the proximity of the AP site influence Ape1 incision
efficiency significantly. Replication protein A (RPA), the major ssDNA-binding protein in mammalian cells, was found to
bind ss AP-DNA with similar affinity as
unmodified ssDNA and ds
AP-DNA with lower affinity. Consistent with their known relative DNA
binding affinities, RPA blocks/inhibits the ss,
but not ds, AP endonuclease
function of Ape1. Moreover, RPA inactivates Ape1 incision activity at an AP
site within the ss region of a fork duplex, but
not a transcription-like bubble intermediate. The data herein suggested a
model whereby RPA selectively suppresses the nontemplated
ss cleavage activity of Ape1 in vivo,
particularly at sites of ongoing replication/recombination, by coating the ssDNA.
PMID: 16356936 [PubMed - in process]
Apurinic/apyrimidinic endonuclease1/redox factor-1 inhibits monocyte adhesion in endothelial cells.
Kim CS, Son SJ, Kim EK, Kim SN, Yoo
DG, Kim HS, Ryoo
SW, Lee SD, Irani
K, Jeon
BH.
Department of Physiology,
OBJECTIVE: Expression of adhesion molecules on endothelial cells and
subsequent monocyte adhesion are initial events
in the development of atherosclerosis. The purpose of this study was to
investigate the role of apurinic/apyrmidinic
endonuclease1/redox factor-1 (APE1/ref-1) in the interaction of monocytes with vascular endothelial cells. METHODS:
Human umbilical vein endothelial cells (HUVECs)
were transfected with an adenovirus encoding
human APE1/ref-1. The effect of APE1/ref-1 overexpression
on monocyte adhesion, vascular cell adhesion
molecule-1 (VCAM-1) protein expression, and intracellular superoxide production in tumor necrosis factor
(TNF)-alpha-activated HUVECs was examined.
RESULTS: Adhesion of the monocytic cell line U937
to TNF-alpha-stimulated HUVECs in which
APE1/ref-1 was overexpressed was suppressed.
APE1/ref-1 overexpression also suppressed
expression of VCAM-1 induced by TNF-alpha. APE1/ref-1-mediated suppression
of VCAM-1 was blocked by pretreatment with the nitric oxide synthase (NOS) inhibitor l-nitroarginine
methyl ester. Furthermore, APE1/ref-1 overexpression
inhibited the TNF-alpha-induced increase in intracellular superoxide and p38 MAPK phosphorylation.
CONCLUSIONS: These data provide evidence that APE1/ref-1 in endothelial
cells mitigates TNF-alpha-induced monocyte
adhesion and expression of vascular cell adhesion molecules, and this
anti-adhesive property of APE1/ref-1 is primarily mediated by a
NOS-dependent mechanism. Furthermore, APE1/ref-1 may inhibit VCAM-1
expression by inhibiting superoxide production
and p38 MAPK activation.