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Table 1 Summary of various phosphorylation and acetylation events of human (hp53) and mouse p53 (mp53), as well as their potential roles in regulating p53 stability
and activity
Phosphorylation sites
Human p53
Corresponding
mouse p53
Potential functions of
the modification
Ser15
Ser18
Ser20
Ser33
Ser46
N/A
Thr81
N/A
Ser315
Ser23
N/A
N/A
Ser34
N/A
Thr76/86
Ser312
Ser376/378
Ser373/375
Ser392
Ser389
Disruption of p53MdM2
interaction Recruitment of
CBP/p 300 p53 acetylation and
nuclear retention
Disruption of p53MdM2 interaction
Activation of p53 activities after
UV radiation
N/A
Stabilization of p53 after UV radiation
N/A
Regulation of p53 activities during cellular
proliferation and DNA damage
Activation of p53 activity through promoting
p53/14-3-3 interaction after IR
Regulation of p53 responses to UV radiation?
Acetylation sites
Lys320
Lys317
Lys370/372/373/
Lys367/369/373/
381/382/386
378/379/383
N/A
Recruitment of coactivators CBP/p300
after DNA damage. Stabilization of p53
after DNA damage
References
51,2830
3335,37,39,52
20,44,53,54
55
53
56
5759
60
6167
42,44,45
30,42,43,46,49,50
p53MDM2 interaction. First, it is possible that phosphorylation of human p53 at Ser20 and mouse p53 at Ser23 have
different roles in regulating p53 stability and activity. However,
several lines of evidence argued against this possibility. The
human p53 knockin mice, in which the core region (aminoacid sequence 33332) of the endogenous mouse p53 was
replaced with the human counterpart, have normal p53
responses to DNA damage and p53-dependent tumor
suppression.41 This indicates that the DNA-damaged-induced
signaling pathways leading to the activation of p53 responses
are highly conserved between human and the mouse. In
addition, the amino-acid sequence between 13 and 27
(human numbering) is identical between human and mouse
p53. Secondly, most previous assays involved the overexpression of mutant p53 in tumor cell lines. It is possible that
tumor cells are defective in certain signaling pathways leading
to the phosphorylation of p53 at other sites, contributing to the
more apparent requirement of Ser20 phosphorylation in p53
stabilization.
A number of other phosphorylation events of mouse and
human p53 have been identified after DNA damage or during
cellular proliferation. The kinases involved in these phosphorylation events and the potential roles of these phosphorylation
events in regulating p53 stability and activity are summarized
in Table 1.
402
DNA Damage
P P P
T55
T81
S315
S392
DBD
Pro-rich
TA
P P
S15 T18
NLS
REG
TET
S315
S376 S392
Replicative Senescence
Cellular Proliferation
b
+
+
CBP/p300
PCAF
P
TA
Ac Ac Ac Ac Ac Ac
Ac
P
Pro-rich
DBD
NLS
TET
REG
Ub Ub Ub Ub Ub Ub
MDM2
Future directions
Recent studies have shown that phospho- or acetylationspecific antibodies, which recognize p53 modified at a
particular site, are indispensable tools to study the regulation
and interaction among various post-translational modification
events. Development of a complete set of these antibodies to
modified mouse and human p53 in the future will be critical
to identify the unique patterns of post-translational modifications induced by a particular stress stimulus and the
interactions between the various post-translational modifications. Overexpression of p53 mutants in tumor cell lines is a
risky experimental approach and the conclusions from such
studies will require verification for their physiological relevance. Studies employing mouse knockin technology could
address the physiological roles of p53 post-translational
modifications, but will represent a major effort. Some
phosphorylation sites within the proline-rich domain of mouse
and human p53 are not conserved. The physiological
403
Acknowledgments
I thank CW Anderson, C Murre and members of my laboratory for critically
reading this manuscript. Supported by grants from DOD Breast Cancer
Research Program and National Cancer Institute.
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