Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P04637 (
p53
)
77,613
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a tumor suppressor that is frequently inactivated in many human cancers. However, the molecular mechanism underlying its growth-inhibitory function remains largely unknown. Here, we report that XAF1 forms a positive feedback loop with
p53
and acts as a molecular switch in
p53
-mediated cell-fate decisions favoring apoptosis over cell-cycle arrest. XAF1 binds directly to the N-terminal proline-rich domain of
p53
and thus interferes with E3 ubiquitin ligase MDM2 binding and ubiquitination of
p53
. XAF1 stimulates homeodomain-interacting protein kinase 2 (HIPK2)-mediated Ser-46 phosphorylation of
p53
by blocking E3 ubiquitin ligase Siah2 interaction with and ubiquitination of HIPK2. XAF1 also steps up the termination of
p53
-mediated cell-cycle arrest by activating
zinc finger protein 313
(
ZNF313
), a p21(WAF1)-targeting ubiquitin E3 ligase. XAF1 interacts with
p53
, Siah2, and
ZNF313
through the zinc finger domains 5, 6, and 7, respectively, and truncated XAF1 isoforms preferentially expressed in cancer cells fail to form a feedback loop with
p53
. Together, this study uncovers a novel role for XAF1 in
p53
stress response, adding a new layer of complexity to the mechanisms by which
p53
determines cell-fate decisions.
...
PMID:XAF1 directs apoptotic switch of p53 signaling through activation of HIPK2 and ZNF313. 2531 37
