Pleckstrin homology-like domain family B member 3 (PHLDB3)

Pleckstrin homology-like domain family B member 3 (PHLDB3) is an oncoprotein that serves as a feedback regulator of the tumor suppressor p53. It is a direct transcriptional target of p53, but functions paradoxically to suppress p53 activity: PHLDB3 binds MDM2, an E3 ubiquitin ligase, enhancing MDM2-mediated ubiquitination and proteasomal degradation of p53 protein. This negative regulation of p53 promotes cell proliferation and inhibits apoptosis, aiding tumor growth and conferring resistance to DNA-damaging chemotherapeutic agents such as doxorubicin and 5-fluorouracil. PHLDB3 is amplified or highly expressed in a variety of cancers, especially those retaining wild-type p53, and its depletion induces cell death and increases drug sensitivity, often with greater effect in p53-positive cells. PHLDB3 may also exert additional p53-independent oncogenic functions. Its activity makes it a promising therapeutic target for overcoming drug resistance in cancer, though targeting it directly could have complexities due to its feedback role in p53 and MDM2 regulation[1][2][4].

Other names

FLJ40193LL5γPleckstrin homology-like domain family B member 3PHLDB3

Drugs enhancing p53 activity (e.g., inhibitors of MDM2-p53 interaction could be affected by PHLDB3's enhancement of p53 degradation) Chemotherapeutic sensitization (PHLDB3 knockdown raises cancer cell sensitivity to DNA-damaging drugs via p53 pathway activation)