Pleckstrin homology domain-containing protein PHLDB3 supports cancer growth via a negative feedback loop involving p53.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28008906.
- Also identified by DOI 10.1038/ncomms13755 and PMC identifier 5196188.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The tumour suppressor p53 transactivates the expression of its target genes to exert its functions. Here, we identify a pleckstrin homology domain-containing protein (PHLDB3)-encoding gene as a p53 target. PHLDB3 overexpression increases proliferation and restrains apoptosis of wild-type p53-harboring cancer cells by reducing p53 protein levels. PHLDB3 binds to MDM2 (mouse double minute 2 homolog) and facilitates MDM2-mediated ubiquitination and degradation of p53. Knockdown of PHLDB3 more efficiently inhibits the growth of mouse xenograft tumours derived from human colon cancer HCT116 cells that contain wild type p53 compared with p53-deficient HCT116 cells, and also sensitizes tumour cells to doxorubicin and 5-Fluorouracil. Analysis of cancer genomic databases reveals that PHLDB3 is amplified and/or highly expressed in numerous human cancers. Altogether, these results demonstrate that PHLDB3 promotes tumour growth by inactivating p53 in a negative feedback fashion and suggest PHLDB3 as a potential therapeutic target in various human cancers.
Medical subject headings
- Feedback, Physiological
- Intracellular Signaling Peptides and Proteins
- Neoplasm Proteins
- Neoplasms
- Pleckstrin Homology Domains
- Tumor Suppressor Protein p53