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Blood, Vol. 95 No. 9 (May 1), 2000:
pp. 2748-2752
PLENARY PAPER
Role of SUMO-1-modified PML in nuclear body formation
Sue Zhong,
Stefan Müller,
Simona Ronchetti,
Paul S. Freemont,
Anne Dejean, and
Pier Paolo Pandolfi
From the Department of Human Genetics and Molecular Biology Program,
Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division,
Graduate School of Medical Sciences, Cornell University, New York, NY;
Unite de Recombinaison et Expression Genetique, INSERM U 163, Institut
Pasteur, Paris, France; and Molecular Structure and
Function Laboratory, Imperial Cancer Research Fund, London, England.
 |
Abstract |
The tumor-suppressive promyelocytic leukemia (PML) protein of acute
promyelocytic leukemia (APL) has served as one of the defining
components of a class of distinctive nuclear bodies (NBs). PML is
delocalized from NBs in APL cells and is degraded in cells infected by
several viruses. In these cells, NBs are disrupted, leading to the
aberrant localization of NB proteins. These results have suggested a
critical role for the NB in immune response and tumor suppression and
raised the question of whether PML is crucial for the formation or
stability of NB. In addition, PML is, among other proteins, covalently
modified by SUMO-1. However, the functional relevance of this
modification is unclear. Here, we show in primary PML / cells of various histologic origins, that in the
absence of PML, several NB proteins such as Sp100, CBP, ISG20, Daxx,
and SUMO-1 fail to accumulate in the NB and acquire aberrant
localization patterns. Transfection of PML in PML/
cells causes the relocalization of NB proteins. By contrast, a PML
mutant that can no longer be modified by SUMO-1 fails to do so and
displays an aberrant nuclear localization pattern. Therefore, PML is
required for the proper formation of the NB. Conjugation to SUMO-1 is a
prerequisite for PML to exert this function. These data shed new light
on both the mechanisms underlying the formation of the NBs and the
pathogenesis of APL.
(Blood. 2000;95:2748-2752)
© 2000 by The American Society of Hematology.
| |
Introduction |
The cell nucleus is compartmentalized into highly
organized domains that are associated with specific nuclear functions.
For example, nucleoli are sites of ribosomal RNA synthesis and
processing, whereas coiled bodies contain spliceosomal small nuclear
ribonucleoproteins plus a subset of other splicing
factors.1 One distinctive class of subnuclear domains,
which appears as punctate speckles under immunofluorescence microscopy,
was originally identified as autoantigens in primary biliary cirrhosis
patients2 and variably named Kremer bodies, nuclear domain
10 (ND10), promyelocytic leukemia protein nuclear bodies (PML
NBs), or PODs (PML oncogenic domains) because subsequent
studies showed that the PML protein of acute promyelocytic leukemia
(APL) is tightly associated with these NBs.3-8 Several NB
components have been recently identified, such as SUMO-1/PIC1, Sp100,
Daxx, ISG20, and CBP.8,9
PML belongs to a family of proteins characterized by the presence of
the RBCC (RING-B-Box-Coiled-coil) motif or tripartite motif,10,11 which consists of a
C3HC4 zinc finger motif (RING finger) and 1 or
2 additional cysteine-rich regions (B-boxes) followed by a predicted
leucine coiled-coil region. PML is specifically up-regulated at the
transcriptional level by type 1 and 2 interferons (IFN), which are
potent growth and tumor suppressive cytokines.12,13 IFN
increases PML expression as well as the size and the number of
NBs.2,8,12-14 More recently, the analysis of mice and cells where PML was inactivated has demonstrated that PML functions as a
growth and tumor suppressor in vivo, at least in part, through its ability to act as a transcriptional coactivator and that PML is
important for multiple apoptotic pathways.15-17
PML is modified by SUMO-1/PIC1 (hereafter referred to for brevity as
SUMO-1), a ubiquitin-like protein that localizes to different cellular
compartments and is covalently bound to various proteins. For example,
SUMO-1 binds to RanGAP1 at the nuclear pore complex18 or to
I B in the cytoplasm.19 SUMO-1 is also found in the
NB, where it covalently modifies NB proteins such as
PML20-22 and Sp100.22 It has been proposed that
SUMO-1 modification can determine the targeting of modified proteins
such as RanGAP1 to a specific cellular compartment.18
The PML gene is fused to the retinoic acid receptor
(RAR) gene in the t(15;17) chromosomal translocation associated with APL.23 As a result of this chromosomal translocation, an
oncogenic PML-RAR fusion protein is generated. The PML-RAR hybrid
retains most of the functional domains of its parental proteins and can heterodimerize with PML.24 In APL cells harboring the
t(15;17) chromosomal translocation, PML, together with other NB
components, is delocalized from NBs into PML-RAR
microspeckles.5-7 Thus, PML-RAR, through
heterodimerization and delocalization of PML, may cause NB proteins to
localize to aberrant nuclear sites. Similarly, upon viral infections,
PML is delocalized along with other NB components.8
For these reasons, and because PML is invariably associated with NBs in
all cells tested, PML has been used as a defining marker for the NB.
However, the role of PML in governing the proper formation or the
stability of the NB has not been investigated. Furthermore, whether in
pathological conditions the targeting of PML by viruses or oncoproteins
is a critical event in the subsequent disorganization of the NB remains
unknown. If this were to be the case, disruption of normal PML
localization would have a pleiotropic effect on the functions of many
NB components. In addition, it is still unclear whether the
modification of PML by SUMO-1 plays a role in the localization of PML
to the NB and, consequently, in NB organization.
In this article, we demonstrate that PML and its modification by SUMO-1
play a critical role in the proper formation of the NB, thus providing
an explanation of the dramatic consequences of PML delocalization in
APL cells.
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Materials and methods |
Primary cell preparation, cell culture, and transfection
Mouse primary embryonic fibroblasts, keratinocytes, and splenocytes
were prepared as previously described.16,25
Cells were split 1 day prior to transfection, whereupon they reached
approximately 70% to 80% confluence. Transfections with pSG5-PML (0.2 µg17), pSG5-3M-PML (0.2 µg), pSG5-PML-RAR,
pEGFP-Sp100 (0.2 µg), or pSG5-HA-ISG20 (0.2 µg) were carried out in
6-well clusters using the Superfect reagent (Qiagen, Chatsworth, CA)
following the manufacturer's instructions. After 24 hours, cells were
trypsinized, transferred to chambered slides, and grown for another 24 hours before further analysis.
Indirect immunofluorescence
Primary mouse embryonic fibroblasts (MEFs) and keratinocytes were
grown in appropriate medium, as described above. Splenocytes were
cytospun for 5 minutes at 1000 rpm directly onto glass slides. Cells
were fixed using 4% paraformaldehyde in phosphate-buffered saline
(PBS) for 20 minutes at room temperature and were permeabilized by
incubating in methanol for 7 minutes at  20°C. After washing 3 times in PBS and blocking in phosphate-buffered saline-Tween 20 (PBST) containing 10% heat-inactivated goat serum, the cells were
incubated for 1 hour at room temperature with an anti-PML antibody
(rabbit polyclonal, cross-reacts with mouse PML15), and/or
an anti-SUMO-1 antibody (mouse monoclonal, cross-reacts with mouse
SUMO-1; a gift from Dr Michael Matunis, Johns Hopkins University,
Baltimore, MD), and/or an anti-Daxx antibody (mouse monoclonal, Santa
Cruz Biotechnologies, Santa Cruz, CA), and/or an anti-Sp100 antiserum
(human origin, cross-reacts with mouse Sp100; a gift from Dr Gerd G. Maul, The Wistar Institute, Philadelphia, PA), and/or an anti-CBP
antibody (rabbit polyclonal, A22, Santa Cruz), and/or an
anti-hemagglutinin (HA) antibody (mouse monoclonal, Roche,
Indianapolis, IN) diluted in the blocking buffer. For
detection, Texas red- or fluorescein-conjugated goat antirabbit,
fluorescein-conjugated horse antimouse, or fluorescein-conjugated mouse
antihuman IgG antibodies (PharMingen, San Diego, CA) were diluted in
blocking buffer containing 1 ng/mL of DAPI. Cells were incubated with
the respective secondary antibody mix for 1 hour at room temperature, washed 3 times in PBS, and covered with Permount mounting medium (Fisher Scientific, Springfield, NJ). Slides were viewed on an Olympus
fluorescence microscope or analyzed by confocal microscopy in the
institute core facility.
Site-directed mutagenesis
The 3M-PML mutant was derived from a human PML complementary
DNA26 (cDNA) cloned in the pSG5 expression vector
(Stratagene, Madison, WI). Arginine-to-lysine mutations at amino acid
positions 65, 160, and 49027 were created using the
QuikChange site-directed mutagenesis kit (Promega, Madison, WI)
according to manufacturer's instructions. The construct was verified
by DNA sequencing.
| |
Results |
Sp100, CBP, ISG20, Daxx, and SUMO-1 fail to accumulate in the NB in
the absence of PML
Because PML is covalently modified by SUMO-1, we performed confocal
immunofluorescence analysis on primary cells obtained from
PML+/+ and PML/ mice with
monoclonal anti-SUMO-1 and polyclonal anti-PML antibodies (see
"Materials and methods"). In PML+/+ MEFs, SUMO-1
colocalized with PML in discrete speckled nuclear regions (Figure
1A). However, SUMO-1 also displayed a
diffuse nuclear and cytoplasmic localization pattern and also
accumulated, unlike PML, in larger nuclear regions (Figure 1A). In
contrast, in PML/ MEFs, SUMO-1 did not
acquire its distinctive speckled nuclear localization pattern, but it
was still readily detected in the nucleus and the cytoplasm in a
diffuse distribution or in larger nuclear aggregates (Figure 1A). The
pronounced nuclear rim staining of SUMO-1 in
PML/ MEFs may reflect the SUMO-1 modification
of RanGAP1, which localizes to the nuclear envelope, whereas the
localization of SUMO-1 in the large nuclear domains may be specific to
certain cell types, such as MEF, because it was not observed in
keratinocytes (Figure 2).
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| Fig 1.
PML is required for the NB localization of SUMO-1, Sp100,
Daxx, CBP, and ISG20.
Primary MEFs were grown on chambered slides before immunofluorescence
analysis. MEFs were double-labeled for PML and (A) SUMO-1, (B) Sp100,
and (C) Daxx. (D) The localization of endogenous CBP in
PML+/+ and PML/ MEFs. (E) The
localization of transfected HA-ISG20 in PML+/+ and
PML/ MEFs. Primary cells were transfected
with HA-ISG20. After 24 hours, cells were harvested and stained for the
HA epitope. Representative confocal micrographs are shown, with the
respective immunofluorescent colors (PML, red;
SUMO-1/Sp100/Daxx/CBP/HA-ISG20, green; DAPI, blue) labeled in the lower
corners of each image. Colocalization is reflected by the yellow color.
Bar: 5 µm.
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| Fig 2.
Transfected PML in PML/ cells recruits
Daxx, SUMO-1, and Sp100 to the NBs.
PML/ keratinocytes were transfected with
pSG5-PML alone or cotransfected with pSG5-PML and pEGFP-Sp100. After 24 hours, cells were harvested and cytospun onto glass slides for
immunofluorescence staining. Representative confocal micrographs are
shown (PML, red; SUMO-1/Daxx/GFP-SP100, green; DAPI, blue). The yellow
color reflects colocalization. The arrow points to a cell transfected
with GFP-Sp100 only. This represents the localization pattern of
transfected Sp100 in PML/ keratinocytes where
this protein aggregates in large patches. Bar: 5 µm.
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To confirm these findings in cells of a different histologic origin, we
studied the localization of PML and SUMO-1 in splenocytes obtained from
PML+/+ and PML/ mice untreated or
activated with concanavalin A (ConA). ConA activation of splenocytes
increases the number and size of the NBs.15,16 In both
ConA-treated and -untreated PML+/+ splenocytes, SUMO-1
colocalized with PML in the NB, whereas in PML/ cells, SUMO-1 displayed an aberrant
nuclear diffuse/microspeckled localization pattern and accumulated in
larger nuclear regions (not shown).
We next tested whether other NB components, such as Sp100, Daxx, CBP,
and ISG20, would be delocalized in the absence of PML.
Sp100 is one of the first NB components identified as an autoantigen
that is prevalent in primary cirrhosis.28 Like PML, Sp100
is also up-regulated by IFN,29 and it can play a role in
IFN-induced immune responses. However, Sp100 does not appear to
physically interact with PML.6 In PML+/+ MEFs,
the Sp100 protein colocalized with PML in the NBs, and it acquired an
aberrant diffused nuclear distribution pattern in
PML/ MEFs (Figure 1B).
Daxx was cloned as an adaptor molecule that can bind to the death
domain of the Fas receptor via its C-terminal end and has been found to
play a role in the potentiation of the Fas pro-apoptotic stimulus.30 We have shown that Daxx can physically interact with PML and localize in the NB.9 In PML+/+
MEFs, Daxx localized in the NBs together with PML but was detected in a
nuclear diffused or patched pattern in PML/
MEFs and keratinocytes, respectively (Figure 1C and Figure 2). It is
noteworthy that in wild-type MEFs Daxx is predominantly nuclear (Figure
1C).
The CBP transcriptional coactivator also localizes in the
NB.31-33 CBP displayed a speckled as well as a diffuse
nuclear localization pattern in PML+/+ MEFs (Figure 1D).
However, in PML/ MEFs, CBP acquired a
microspeckled and a diffuse nuclear distribution (Figure 1D).
ISG20 was cloned as an IFN-induced protein, which was found to
accumulate in the PML NB.34 Because no antibody against the murine ISG20 is yet available, the nuclear localization of ISG20 was
studied in PML+/+ and PML/ MEFs
transiently transfected with an HA-tagged ISG20 expression vector
(Figure 1E). HA-ISG20 localized in the NBs in PML+/+ MEFs
but was detected in a nuclear diffused pattern in
PML/ MEFs (Figure 1E).
Thus, PML is required for the proper nuclear compartmentalization of NB components.
Transfection of PML in PML/ cells restores
normal localization of NB components
To further characterize the role of PML in the localization of the
above proteins in the NB, PML/ keratinocytes
(Figure 2) and MEFs (not shown) were transiently transfected with PML.
After 24 hours, cells were fixed and subjected to immunofluorescence
analysis with a polyclonal anti-PML antibody (See "Materials and
methods"). Using this antibody, transfected or untransfected
PML/ cells could be easily distinguished
(Figure 2). In the PML-transfected cells, endogenous NB components such
as, for instance, Daxx and SUMO-1, reacquired a speckled pattern, which
overlapped with the one of PML (Figure 2). Similarly, whereas
transfected GFP-SP100 formed large nuclear aggregates in
PML/ cells, cotransfection of PML along with
GFP-Sp100 in PML/ cells restored the NB
localization of GFP-Sp100 (Figure 2).
SUMOylation of PML is a prerequisite for NB formation
The PML protein forms covalent bonds with SUMO-1 at 3 amino acid
positions: 65, 160, and 490 through lysine residues.27 Because the SUMOylated PML is tightly associated with the nuclear matrix but the unmodified form of PML is not, it has been proposed that
SUMO modification plays an important role for docking PML in the
NB.21 To clarify the role of PML SUMOylation in directing PML NB localization, we generated a PML mutant (3M-PML) that is no
longer SUMO-modified by mutating amino acid positions 65, 160, and 490 from lysines to arginines (Figure
3A). The arginine residue was chosen for
its close resemblance to lysine in structure and charge. Western blot
analysis of the transfected 3M-PML mutant protein in HeLa and COS-1
cells indicated that this protein was not SUMOylated (not shown). We
then transiently transfected wild-type PML or 3M-PML in
PML/ primary cells. After 24 hours, cells
were harvested and subjected to immunofluorescence analysis using the
anti-PML polyclonal antibody. In PML/
keratinocytes, transfected 3M-PML accumulated in aberrant nuclear aggregates, and wild-type PML localized in nuclear speckles (Figure 3B). Wild-type PML accumulated on average in 14.4 ± 9.5 nuclear speckles per cell (n = 100). The average number of PML NBs in PML+/+ keratinocytes was 15.2 ± 8.3 (n = 100). By
contrast, the 3M-PML formed, on average, 1.6 ± 0.9 nuclear
aggregates per cell (n = 100). Furthermore, the size of the speckles
observed in cells transfected with wild-type PML was similar to the
size of PML-NBs in wild-type keratinocytes (0.3-0.5 µm) and much
smaller than that of the 3M-PML aggregates (1-2 µm). Thus,
SUMOylation of PML is crucial for PML to localize in the NB.
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| Fig 3.
3M-PML forms aberrant nuclear aggregates.
(A) Schematic structure of PML and 3M-PML. Wild-type PML can be
modified by SUMO-1 at amino acid positions 65, 160, and 490 through 3 lysines (K). In 3M-PML, the 3 lysines were mutated to arginines (R). R:
RING finger domain. B1, B2: B-boxes. Coiled coil: helical coiled-coil
region. S/P: serine/proline-rich region. (B) Localization of
transfected wild-type PML and 3M-PML. Representative confocal
micrographs are shown, with the immunofluorescent colors (PML/3M-PML,
red; DAPI, blue) labeled in the lower corners of each image. Bar: 5 µm.
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We next studied if unSUMOylated PML can still recruit NB components,
such as Daxx, by performing immunofluorescence staining of endogenous
Daxx and SUMO-1 in 3M-PML-transfected PML/
keratinocytes. In contrast to wild-type PML (Figure 2), 3M-PML failed
to colocalize with Daxx, SUMO-1, and GFP-Sp100 (Figure 4), suggesting that SUMO modification is a
prerequisite for PML to recruit other components, such as Daxx and
Sp100, to the NB.
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| Fig 4.
3M-PML fails to recruit Daxx, SUMO-1, and Sp100 to the
NBs.
PML/ keratinocytes were transfected with
pSG5-3M-PML alone or cotransfected with pSG5-3M-PML and pEGFP-Sp100.
After 24 hours, cells were harvested and cytospun onto glass slides for
immunofluorescence staining. Representative confocal pictures are
shown, with the immunofluorescent colors (PML, red;
SUMO-1/Daxx/GFP-Sp100, green; DAPI, blue) labeled in the
lower corners of each image. Bar: 5 µm.
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PML-RAR can recruit NB components to nuclear microspeckled sites
in the absence of PML
In APL cells, PML-RAR delocalizes PML and other NB members, such
as SUMO-1 and Daxx, to microspeckled nuclear regions.5-7 It
has been suggested that the accumulation of NB components in microspeckles might be due to the ability of PML-RAR to
heterodimerize with PML.5-7 To further understand the role
of PML in determining the subnuclear localization of PML-RAR and in
the ability of the fusion protein to determine aberrant localization of
NB components, we transfected PML-RAR in
Pml+/+ and
Pml/ MEFs. In the absence of PML,
PML-RAR still formed nuclear microspeckles that were
indistinguishable from the ones in Pml+/+
cells (Figure 5 and not shown). Endogenous
SUMO-1 and Daxx colocalized with overexpressed PML-RAR in nuclear
microspeckles in Pml/ cells (Figure
5B). Because PML-RAR contains a large portion of PML and 2 or 3 PML
SUMOylation sites depending on the breakpoint within the PML
locus23,24 (3 in the PML-RAR isoform that we have used;
see "Materials and methods") and it can be
SUMOylated,21 the recruitment of SUMO-1 and Daxx is
presumably due to the PML moiety of PML-RAR. It must be noted,
however, that in NB4 APL cells expressing PML-RAR, Daxx was found
delocalized from the NBs but did not completely colocalize with
PML-RAR.9
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| Fig 5.
In Pml/ cells, PML-RAR
accumulates in nuclear microspeckles and recruits endogenous SUMO-1 and
Daxx to these aberrant sites.
PML/ MEFs were transfected with
pSG5-PML-RAR. After 24 hours, cells were harvested and cytospun onto
glass slides for immunofluorescence analysis. Representative confocal
pictures are shown, with the immunofluorescent colors (PML-RAR, red;
SUMO-1/Daxx, green; DAPI, blue) labeled in the lower
corners of each image. Bar: 5 µm.
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| |
Discussion |
The PML NBs have been intensively studied during the past 10 years,
mostly because of the dynamics of these subnuclear structures during
viral infections and in human cancer. However, the function of the NB
remains unclear. The variety of the NB components suggests a wide range
of possible biological roles, including tumor and growth suppression,
transcription regulation, and cellular immune response via
IFN.8 Also, it has been suggested that these bodies can
accumulate inactive proteins and release them upon certain signals.35 One fundamental question that needs to be
addressed, however, is whether certain proteins act as constitutive
components of the NB and are required for the integrity and stability
of this nuclear structure. Here, we demonstrate that PML is critical for several proteins to localize in the NB, including Sp100, Daxx, CBP,
and ISG20. Other proteins that have been recently found to colocalize
with PML in the NB, such as the BLM DNA helicase implicated in the
pathogenesis of the Bloom syndrome, are also delocalized in the absence
of PML.36 Both BLM and Sp100 do not appear to directly
interact with PML.6,36 However, it is possible that BLM and
Sp100 interact with other NB components. It remains to be seen if other
NB components might aggregate in NB-like structures, even in the
absence of PML, and whether these molecules are required for PML
accumulation in the NB. The identification of such proteins will
further clarify the chain of events required for NB nucleation.
It has been suggested that only the SUMO-1-modified PML is tightly
associated with the nuclear matrix and that, therefore, PML is
localized to the NB as a consequence of its modification.21 This mechanism of recruitment could apply to other NB components. SUMO-1 would therefore serve to direct the proper compartmentalization of proteins into the NB.21 While this article was in
revision, it was reported that, in HEp-2 cells, transfected 3M-PML
mutant protein accumulated in NBs.37 However, because HEp-2
cells express endogenous PML, it is likely that the 3M-PML mutant
protein formed heterodimeric complexes with the endogenous wild-type
PML and was thus recruited to the NBs. In contrast, by using
PML/ cells, we conclusively demonstrate that
PML needs to be modified by SUMO-1 to acquire an NB-speckled
localization pattern. Furthermore, our data also demonstrate that the
SUMO-1 modification of Sp100 is not sufficient for this protein to
acquire an NB localization in the absence of PML. This is also
supported by the finding that SUMOylation of Sp100 is not necessary for
its NB localization because an Sp100 mutant that can no longer be
SUMOylated still localizes in the NB.38 Thus, although our
data support a critical role for SUMOylation in directing the NB
localization of modified proteins, they suggest that some of the
modified NB components still depend on PML to accumulate into the NB.
The notion that SUMO-1 is necessary but not sufficient to determine the
localization of its targets is in agreement with the fact that modified
proteins have been found in various locations, such as the NB, the
nuclear pore (RanGAP118), and the cytosol
(IB19)b and that, as aforementioned, at least in the
case of Sp100, lack of modification does not impair proper nuclear
localization.38 It is also noteworthy that not every
SUMO-1-modified NB component is essential for the localization of
other NB proteins. For example, when NT2 cells differentiate into nerve
cells in vitro, Sp100 is not expressed while PML is still localized to
the NBs.35 Hence, it is not just the relative amount of
SUMO-1-interacting proteins in the NBs but, rather, the specific
function of PML that determines the localization of the
SUMO-1-modified NB proteins. We therefore propose a hierarchy of
events by which PML needs to be first SUMOylated in order to accumulate
in the NBs, where it subsequently recruits additional NB components.
Our findings also provide an explanation for why the delocalization of
PML from the NB by PML-RAR in APL blasts, or the degradation of PML
upon viral infections, results in the delocalization of multiple
proteins from the NB.2,5-7 In some instances, PML-RAR could induce the delocalization of NB proteins directly, possibly through the PML moiety. We have recently reported that the
PML/ mice are viable but are more susceptible
to tumorigenesis and bacterial infections.15
PML/ cells exhibit a marked growth
advantage.15 In addition, PML/
mice and cells are protected from multiple apoptotic
stimuli.16 Thus, PML appears to regulate multiple cellular
functions. Some of these tumor-suppressive functions could be
attributed to the ability of PML to act as a transcriptional
cofactor.17 One implication of the findings herein is that
the pleiotropic effects of PML inactivation might be due to the
disruption of several pathways regulated by proteins that depend on PML
to be properly compartmentalized in the nucleus in order to exert their
normal functions. The fact that Daxx and Sp100 are delocalized from the
NBs in the absence of PML may be particularly relevant because Daxx may
have a role regulating programmed cell death,30-39 whereas
Sp100 is up-regulated by interferons29 and thus possibly
mediates the growth-suppressive and immunologic functions of these
cytokines. Delocalization of CBP in the PML/
cells may contribute to their impaired responses to
retinoic acid-induced transcription.17
Therefore, PML might exert some of its biological functions through the
regulation of the formation of the NB, and PML-RAR may
contribute to leukemogenesis through its ability to interfere with
these processes by interacting with and sequestering PML.
| |
Acknowledgments |
We thank Michael Antoniou, Maria Barna, Letizia Longo, Katia Manova,
Gerd G. Maul, Michael Matunis, and Zhu Gang Wang for advice, materials,
and help in some experiments.
| |
Footnotes |
Submitted October 18, 1999; accepted January 5, 2000.
Supported by the National Cancer Institute (CA-08748,
CA-71692, and CA74031 awarded to P.P.P.). S.M. was supported by a
fellowship from the Association for International Cancer Research.
S.R. was partially supported by Centro Nazionale per la Ricerca.
P.P.P. is a Scholar of the Leukemia Society of America.
Reprints: Pier Paolo Pandolfi, Department of Human
Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer
Center, Sloan-Kettering Division, Graduate School of Medical Sciences,
Cornell University, 1275 York Ave, New York, NY 10021; e-mail:
p-pandolfi{at}ski.mskcc.org.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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The ProMiscuousLy (PML) exciting nuclear protein has another partner
Blood,
May 1, 2005;
105(9):
3393 - 3394.
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P. Salomoni, R. Bernardi, S. Bergmann, A. Changou, S. Tuttle, and P. P. Pandolfi
The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage
Blood,
May 1, 2005;
105(9):
3686 - 3690.
[Abstract]
[Full Text]
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C.-C. Chang, D.-Y. Lin, H.-I Fang, R.-H. Chen, and H.-M. Shih
Daxx Mediates the Small Ubiquitin-like Modifier-dependent Transcriptional Repression of Smad4
J. Biol. Chem.,
March 18, 2005;
280(11):
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[Abstract]
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H. Takahashi, S. Hatakeyama, H. Saitoh, and K. I. Nakayama
Noncovalent SUMO-1 Binding Activity of Thymine DNA Glycosylase (TDG) Is Required for Its SUMO-1 Modification and Colocalization with the Promyelocytic Leukemia Protein
J. Biol. Chem.,
February 18, 2005;
280(7):
5611 - 5621.
[Abstract]
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C. B. Gocke, H. Yu, and J. Kang
Systematic Identification and Analysis of Mammalian Small Ubiquitin-like Modifier Substrates
J. Biol. Chem.,
February 11, 2005;
280(6):
5004 - 5012.
[Abstract]
[Full Text]
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S. GRISENDI and P.P. PANDOLFI
Two Decades of Cancer Genetics: From Specificity to Pleiotropic Networks
Cold Spring Harb Symp Quant Biol,
January 1, 2005;
70(0):
83 - 91.
[Abstract]
[PDF]
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E. A. Andrews, J. Palecek, J. Sergeant, E. Taylor, A. R. Lehmann, and F. Z. Watts
Nse2, a Component of the Smc5-6 Complex, Is a SUMO Ligase Required for the Response to DNA Damage
Mol. Cell. Biol.,
January 1, 2005;
25(1):
185 - 196.
[Abstract]
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G. A. Smolen, M. T. Vassileva, J. Wells, M. J. Matunis, and D. A. Haber
SUMO-1 Modification of the Wilms' Tumor Suppressor WT1
Cancer Res.,
November 1, 2004;
64(21):
7846 - 7851.
[Abstract]
[Full Text]
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M. Smith, V. Bhaskar, J. Fernandez, and A. J. Courey
Drosophila Ulp1, a Nuclear Pore-associated SUMO Protease, Prevents Accumulation of Cytoplasmic SUMO Conjugates
J. Biol. Chem.,
October 15, 2004;
279(42):
43805 - 43814.
[Abstract]
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J. Song, L. K. Durrin, T. A. Wilkinson, T. G. Krontiris, and Y. Chen
Identification of a SUMO-binding motif that recognizes SUMO-modified proteins
PNAS,
October 5, 2004;
101(40):
14373 - 14378.
[Abstract]
[Full Text]
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L.-K. Chang, Y.-H. Lee, T.-S. Cheng, Y.-R. Hong, P.-J. Lu, J. J. Wang, W.-H. Wang, C.-W. Kuo, S. S.-L. Li, and S.-T. Liu
Post-translational Modification of Rta of Epstein-Barr Virus by SUMO-1
J. Biol. Chem.,
September 10, 2004;
279(37):
38803 - 38812.
[Abstract]
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G. Gill
SUMO and ubiquitin in the nucleus: different functions, similar mechanisms?
Genes & Dev.,
September 1, 2004;
18(17):
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[Abstract]
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O. G. Engelhardt, H. Sirma, P.-P. Pandolfi, and O. Haller
Mx1 GTPase accumulates in distinct nuclear domains and inhibits influenza A virus in cells that lack promyelocytic leukaemia protein nuclear bodies
J. Gen. Virol.,
August 1, 2004;
85(8):
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[Abstract]
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M. Nevels, W. Brune, and T. Shenk
SUMOylation of the Human Cytomegalovirus 72-Kilodalton IE1 Protein Facilitates Expression of the 86-Kilodalton IE2 Protein and Promotes Viral Replication
J. Virol.,
July 15, 2004;
78(14):
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[Abstract]
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H.-R. Lee, D.-J. Kim, J.-M. Lee, C. Y. Choi, B.-Y. Ahn, G. S. Hayward, and J.-H. Ahn
Ability of the Human Cytomegalovirus IE1 Protein To Modulate Sumoylation of PML Correlates with Its Functional Activities in Transcriptional Regulation and Infectivity in Cultured Fibroblast Cells
J. Virol.,
June 15, 2004;
78(12):
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[Abstract]
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K. A. Wong, R. Kim, H. Christofk, J. Gao, G. Lawson, and H. Wu
Protein Inhibitor of Activated STAT Y (PIASy) and a Splice Variant Lacking Exon 6 Enhance Sumoylation but Are Not Essential for Embryogenesis and Adult Life
Mol. Cell. Biol.,
June 15, 2004;
24(12):
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[Abstract]
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F. Bernassola, P. Salomoni, A. Oberst, C. J. Di Como, M. Pagano, G. Melino, and P. P. Pandolfi
Ubiquitin-dependent Degradation of p73 Is Inhibited by PML
J. Exp. Med.,
June 7, 2004;
199(11):
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[Abstract]
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S. Tashiro, A. Muto, K. Tanimoto, H. Tsuchiya, H. Suzuki, H. Hoshino, M. Yoshida, J. Walter, and K. Igarashi
Repression of PML Nuclear Body-Associated Transcription by Oxidative Stress-Activated Bach2
Mol. Cell. Biol.,
April 15, 2004;
24(8):
3473 - 3484.
[Abstract]
[Full Text]
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R. Hagglund and B. Roizman
Role of ICP0 in the Strategy of Conquest of the Host Cell by Herpes Simplex Virus 1
J. Virol.,
March 1, 2004;
78(5):
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C. Gurrieri, P. Capodieci, R. Bernardi, P. P. Scaglioni, K. Nafa, L. J. Rush, D. A. Verbel, C. Cordon-Cardo, and P. P. Pandolfi
Loss of the Tumor Suppressor PML in Human Cancers of Multiple Histologic Origins
J Natl Cancer Inst,
February 18, 2004;
96(4):
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[Abstract]
[Full Text]
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K. A. Becker, L. Florin, C. Sapp, G. G. Maul, and M. Sapp
Nuclear Localization but Not PML Protein Is Required for Incorporation of the Papillomavirus Minor Capsid Protein L2 into Virus-Like Particles
J. Virol.,
February 1, 2004;
78(3):
1121 - 1128.
[Abstract]
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J. H. Yu, A. Nakajima, H. Nakajima, L. R. Diller, K. D. Bloch, and D. B. Bloch
Restoration of Promyelocytic Leukemia Protein-Nuclear Bodies in Neuroblastoma Cells Enhances Retinoic Acid Responsiveness
Cancer Res.,
February 1, 2004;
64(3):
928 - 933.
[Abstract]
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A. Rosendorff, D. Illanes, G. David, J. Lin, E. Kieff, and E. Johannsen
EBNA3C Coactivation with EBNA2 Requires a SUMO Homology Domain
J. Virol.,
January 1, 2004;
78(1):
367 - 377.
[Abstract]
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H. Zhu, L. Wu, and C. G. Maki
MDM2 and Promyelocytic Leukemia Antagonize Each Other through Their Direct Interaction with p53
J. Biol. Chem.,
December 5, 2003;
278(49):
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[Abstract]
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C. H. Eskiw, G. Dellaire, J. S. Mymryk, and D. P. Bazett-Jones
Size, position and dynamic behavior of PML nuclear bodies following cell stress as a paradigm for supramolecular trafficking and assembly
J. Cell Sci.,
November 1, 2003;
116(21):
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[Abstract]
[Full Text]
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R. Tomasini, A. A. Samir, A. Carrier, D. Isnardon, B. Cecchinelli, S. Soddu, B. Malissen, J.-C. Dagorn, J. L. Iovanna, and N. J. Dusetti
TP53INP1s and Homeodomain-interacting Protein Kinase-2 (HIPK2) Are Partners in Regulating p53 Activity
J. Biol. Chem.,
September 26, 2003;
278(39):
37722 - 37729.
[Abstract]
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X. Wei, Z. K. Yu, A. Ramalingam, S. R. Grossman, J. H. Yu, D. B. Bloch, and C. G. Maki
Physical and Functional Interactions between PML and MDM2
J. Biol. Chem.,
August 1, 2003;
278(31):
29288 - 29297.
[Abstract]
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A. V. Chee, P. Lopez, P. P. Pandolfi, and B. Roizman
Promyelocytic Leukemia Protein Mediates Interferon-Based Anti-Herpes Simplex Virus 1 Effects
J. Virol.,
June 15, 2003;
77(12):
7101 - 7105.
[Abstract]
[Full Text]
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Z.-X. Xu, A. Timanova-Atanasova, R.-X. Zhao, and K.-S. Chang
PML Colocalizes with and Stabilizes the DNA Damage Response Protein TopBP1
Mol. Cell. Biol.,
June 15, 2003;
23(12):
4247 - 4256.
[Abstract]
[Full Text]
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Q. Tang, L. Li, A. M. Ishov, V. Revol, A. L. Epstein, and G. G. Maul
Determination of Minimum Herpes Simplex Virus Type 1 Components Necessary To Localize Transcriptionally Active DNA to ND10
J. Virol.,
May 15, 2003;
77(10):
5821 - 5828.
[Abstract]
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Y. Hirano, S. Murata, K. Tanaka, M. Shimizu, and R. Sato
Sterol Regulatory Element-binding Proteins Are Negatively Regulated through SUMO-1 Modification Independent of the Ubiquitin/26 S Proteasome Pathway
J. Biol. Chem.,
May 2, 2003;
278(19):
16809 - 16819.
[Abstract]
[Full Text]
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V. Hietakangas, J. K. Ahlskog, A. M. Jakobsson, M. Hellesuo, N. M. Sahlberg, C. I. Holmberg, A. Mikhailov, J. J. Palvimo, L. Pirkkala, and L. Sistonen
Phosphorylation of Serine 303 Is a Prerequisite for the Stress-Inducible SUMO Modification of Heat Shock Factor 1
Mol. Cell. Biol.,
April 15, 2003;
23(8):
2953 - 2968.
[Abstract]
[Full Text]
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W.-S. Wu, Z.-X. Xu, W. N. Hittelman, P. Salomoni, P. P. Pandolfi, and K.-S. Chang
Promyelocytic Leukemia Protein Sensitizes Tumor Necrosis Factor alpha -Induced Apoptosis by Inhibiting the NF-kappa B Survival Pathway
J. Biol. Chem.,
March 28, 2003;
278(14):
12294 - 12304.
[Abstract]
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[PDF]
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A. Chauchereau, L. Amazit, M. Quesne, A. Guiochon-Mantel, and E. Milgrom
Sumoylation of the Progesterone Receptor and of the Steroid Receptor Coactivator SRC-1
J. Biol. Chem.,
March 28, 2003;
278(14):
12335 - 12343.
[Abstract]
[Full Text]
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L. D. Wood, B. J. Irvin, G. Nucifora, K. S. Luce, and S. W. Hiebert
Small ubiquitin-like modifier conjugation regulates nuclear export of TEL, a putative tumor suppressor
PNAS,
March 18, 2003;
100(6):
3257 - 3262.
[Abstract]
[Full Text]
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L. Berthoux, G. J. Towers, C. Gurer, P. Salomoni, P. P. Pandolfi, and J. Luban
As2O3 Enhances Retroviral Reverse Transcription and Counteracts Ref1 Antiviral Activity
J. Virol.,
March 1, 2003;
77(5):
3167 - 3180.
[Abstract]
[Full Text]
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S. J. Baker
Small Unstable Apoptotic Protein, an Apoptosis-associated Protein, Suppresses Proliferation of Myeloid Cells
Cancer Res.,
February 1, 2003;
63(3):
705 - 712.
[Abstract]
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I. Nefkens, D. G. Negorev, A. M. Ishov, J. S. Michaelson, E. T. H. Yeh, R. M. Tanguay, W. E. G. Muller, and G. G. Maul
Heat shock and Cd2+ exposure regulate PML and Daxx release from ND10 by independent mechanisms that modify the induction of heat-shock proteins 70 and 25 differently
J. Cell Sci.,
February 1, 2003;
116(3):
513 - 524.
[Abstract]
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D. Bailey and P. O'Hare
Herpes simplex virus 1 ICP0 co-localizes with a SUMO-specific protease
J. Gen. Virol.,
December 1, 2002;
83(12):
2951 - 2964.
[Abstract]
[Full Text]
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N. Madani, R. Millette, E. J. Platt, M. Marin, S. L. Kozak, D. B. Bloch, and D. Kabat
Implication of the Lymphocyte-Specific Nuclear Body Protein Sp140 in an Innate Response to Human Immunodeficiency Virus Type 1
J. Virol.,
October 2, 2002;
76(21):
11133 - 11138.
[Abstract]
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P. Lopez, R. J. Jacob, and B. Roizman
Overexpression of Promyelocytic Leukemia Protein Precludes the Dispersal of ND10 Structures and Has No Effect on Accumulation of Infectious Herpes Simplex Virus 1 or Its Proteins
J. Virol.,
August 12, 2002;
76(18):
9355 - 9367.
[Abstract]
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A. M. Ishov, O. V. Vladimirova, and G. G. Maul
Daxx-Mediated Accumulation of Human Cytomegalovirus Tegument Protein pp71 at ND10 Facilitates Initiation of Viral Infection at These Nuclear Domains
J. Virol.,
June 27, 2002;
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7705 - 7712.
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A. Gravel, J. Gosselin, and L. Flamand
Human Herpesvirus 6 Immediate-Early 1 Protein Is a Sumoylated Nuclear Phosphoprotein Colocalizing with Promyelocytic Leukemia Protein-associated Nuclear Bodies
J. Biol. Chem.,
May 24, 2002;
277(22):
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V. S. Lalioti, S. Vergarajauregui, D. Pulido, and I. V. Sandoval
The Insulin-sensitive Glucose Transporter, GLUT4, Interacts Physically with Daxx. TWO PROTEINS WITH CAPACITY TO BIND Ubc9 AND CONJUGATED TO SUMO1
J. Biol. Chem.,
May 24, 2002;
277(22):
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C. Wasylyk, S. E. Schlumberger, P. Criqui-Filipe, and B. Wasylyk
Sp100 Interacts with ETS-1 and Stimulates Its Transcriptional Activity
Mol. Cell. Biol.,
April 15, 2002;
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2687 - 2702.
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A. V. Emelyanov, C. R. Kovac, M. A. Sepulveda, and B. K. Birshtein
The Interaction of Pax5 (BSAP) with Daxx Can Result in Transcriptional Activation in B Cells
J. Biol. Chem.,
March 22, 2002;
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C. Shiels, S. A. Islam, R. Vatcheva, P. Sasieni, M. J. E. Sternberg, P. S. Freemont, and D. Sheer
PML bodies associate specifically with the MHC gene cluster in interphase nuclei
J. Cell Sci.,
March 12, 2002;
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H. Saitoh, M. D. Pizzi, and J. Wang
Perturbation of SUMOlation Enzyme Ubc9 by Distinct Domain within Nucleoporin RanBP2/Nup358
J. Biol. Chem.,
February 8, 2002;
277(7):
4755 - 4763.
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V. Bhaskar, M. Smith, and A. J. Courey
Conjugation of Smt3 to Dorsal May Potentiate the Drosophila Immune Response
Mol. Cell. Biol.,
January 15, 2002;
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492 - 504.
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J. Lin, E. Johannsen, E. Robertson, and E. Kieff
Epstein-Barr Virus Nuclear Antigen 3C Putative Repression Domain Mediates Coactivation of the LMP1 Promoter with EBNA-2
J. Virol.,
January 1, 2002;
76(1):
232 - 242.
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Y. Xu, J.-H. Ahn, M. Cheng, C. M. apRhys, C.-J. Chiou, J. Zong, M. J. Matunis, and G. S. Hayward
Proteasome-Independent Disruption of PML Oncogenic Domains (PODs), but Not Covalent Modification by SUMO-1, Is Required for Human Cytomegalovirus Immediate-Early Protein IE1 To Inhibit PML-Mediated Transcriptional Repression
J. Virol.,
November 15, 2001;
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V. Lallemand-Breitenbach, J. Zhu, F. Puvion, M. Koken, N. Honore, A. Doubeikovsky, E. Duprez, P. P. Pandolfi, E. Puvion, P. Freemont, et al.
Role of Promyelocytic Leukemia (Pml) Sumolation in Nuclear Body Formation, 11s Proteasome Recruitment, and as2O3-Induced Pml or Pml/Retinoic Acid Receptor {alpha} Degradation
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June 18, 2001;
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J.-S. Seeler, A. Marchio, R. Losson, J. M. P. Desterro, R. T. Hay, P. Chambon, and A. Dejean
Common Properties of Nuclear Body Protein SP100 and TIF1{alpha} Chromatin Factor: Role of SUMO Modification
Mol. Cell. Biol.,
May 15, 2001;
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[Abstract]
[Full Text]
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Top
Abstract
Introduction