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Target Concepts:
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Query: UNIPROT:P43146 (
tumour suppressor
)
5,935
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
p53 apoptosis effector related to PMP-22
(
PERP
) is a transcriptional target gene of p53
tumour suppressor
that is specifically induced during apoptosis and not during cell cycle arrest. In primary uveal melanoma (UM), the most common intraocular malignancy in adults that has a reportedly unaffected signalling pathway upstream of and including p53,
PERP
expression is down-regulated in the metastatic monosomy 3-type tumours, compared with the less aggressive disomy 3-type tumours. Here, we demonstrate experimentally, by the use of full-length
PERP
-green fluorescent protein (GFP) fusions and real-time confocal microscopy, the intracellular targeting and plasma membrane localization of
PERP
in living UM cells and show that expression of
PERP
induces caspase-mediated apoptosis in UM cells. Induction of
PERP
expression in GFP-
PERP
-transfected UM cells leads to increased levels of cleaved caspase-8 forms, as well as to reduction of its full-length substrate Bid, but not to detectable processing of caspase-9. The levels of mature caspase-8, -9 and -3 proteins significantly correlate with
PERP
expression levels in primary UMs. Transcriptional profiling of
PERP
and caspase-8 in tumour specimens indicates that the positive association of
PERP
and caspase-8 proteins is a consequence of post-translational processing, most likely at the level of caspase-8 cleavage, and not of increased transcription of pro-caspase-8. We conclude that
PERP
expression leads to activation of an extrinsic receptor-mediated apoptotic pathway, with a possible subsequent engagement of the intrinsic apoptotic pathway. The findings underline the apoptotic pathway mediated by
PERP
as a critical mechanism employed by UM tumours to modulate susceptibility to apoptosis.
...
PMID:P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma. 1904 Apr 20
The tetraspan plasma membrane protein PERP (
p53 apoptosis effector related to PMP22
) is a lesser-known transcriptional target of p53 and p63. A member of the PMP22/GAS3/EMP membrane protein family, PERP was originally identified as a p53 target specifically trans-activated during apoptosis, but not during cell-cycle arrest. Several studies have since shown downregulation of PERP expression in numerous cancers, suggesting that PERP is a
tumour suppressor
protein. This review focusses on the important advances made in elucidating the mechanisms regulating PERP expression and its function as a
tumour suppressor
in diverse human cancers, including breast cancer and squamous cell carcinoma. Investigating PERP's role in clinically-aggressive uveal melanoma has revealed that PERP engages a positive-feedback loop with p53 to regulate its own expression, and that p63 is required beside p53 to achieve pro-apoptotic levels of PERP in this cancer. Furthermore, the recent discovery of the apoptosis-mediating interaction of PERP with SERCA2b at the plasma membrane-endoplasmic reticulum interface demonstrates a novel mechanism of PERP stabilisation, and how PERP can mediate Ca
2+
signalling to facilitate apoptosis. The multi-faceted role of PERP in cancer, involving well-documented functions in mediating apoptosis and cell-cell adhesion is discussed, alongside PERP's emerging roles in epithelial-mesenchymal transition, and PERP crosstalk with inflammation signalling pathways, and other signalling pathways. The potential for restoring PERP expression as a means of cancer therapy is also considered.
...
PMID:PERP-ing into diverse mechanisms of cancer pathogenesis: Regulation and role of the p53/p63 effector PERP. 3267 66
