Multiple Modes of Mdmx Regulation Affect P53 Activation

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ProQuest, 2008 - 214 pages
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MDMX has emerged as a negative regulator of p53 transcriptional activity following DNA damage, loss of ribosomal integrity, and aberrant mitogenic signaling. Disruption of rRNA biogenesis by ribosomal stress activates p53 by releasing ribosomal proteins from nucleoli which bind MDM2 and inhibit p53 degradation. We found that p53 activation by ribosomal stress requires degradation of MDMX by MDM2. This occurs by L11 binding to the acidic domain of MDM2 which promotes its E3 ligase function preferentially towards MDMX. Further, unlike DNA damage which regulates MDMX stability through ATM-dependent phosphorylation events, ribosomal stress does not require MDMX phosphorylation suggesting p53 may be more sensitive to suppression by MDMX under these conditions. Indeed, we find that tumor cells overexpressing MDMX are less sensitive to ribosomal stress-induced growth arrest by the addition of actinomycin D due to formation of inactive p53--MDMX complexes that fail to transcriptionally activate downstream targets such as p21. Knockdown of MDMX increases sensitivity to actinomycin D, whereas MDMX overexpression abrogates p53 activation. Furthermore, MDMX expression promotes resistance to the chemotherapeutic agent 5-fluorouracil (5-FU), which at low concentrations activates p53 by inducing ribosomal stress without significant DNA damage signaling. Knockdown of MDMX abrogates HCT116 tumor xenograft formation in nude mice. MDMX overexpression does not accelerate tumor growth but increases resistance to 5-FU treatment in vivo.
  

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Contents

P53 Signaling
8
P53 Regulation
15
Prevalence of p53 mutation by site
24
Structure of MDM2
35
MDM2 Regulation by Ribosomal Stress
42
Comparison of the Structure of MDM2 versus MDMX
46
MDMXMDM2p53 pathway following DNA damage
53
Materials Methods
62
Actinomycin D and 5FU do not induce DNA Damage
83
Ribosomal Stress does not Induce MDMX S367 phosphorylation
84
Ribosomal Stress induced MDMX degradation does not require CHK2 85 Figure 15 L11 promotes MDMX ubiquitination
86
MDMX degradation by ribosomal stress requires MDM2
87
MDM2 and L11 mediate MDMX down regulation by ribosomal stress
88
L11 is required for MDMX degradation in the presence of ActD
89
MDM2305S mutant does not bind to L11
90
stress
93

Mdmx Regulation of P53 Response to Ribosomal Stress
78
Differential binding of ribosomal proteins to MDM2 and MDMX
79
L11 binds to MDM2 not MDMX
80
Down regulation of MDMX by ribosomal stress
81
MDMX is degraded by ribosomal stress
82
ribosomal stress
102
Regulation of Mdmx Expression by Mitogenic Signaling
127
promoter
152
List of References
162
Copyright

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