p88

Nup88 (also known as p88) is a non-FG repeat nucleoporin localized to the cytoplasmic face of the nuclear pore complex (NPC). Its overexpression is a hallmarks of various human malignancies, where it functions through distinct mechanisms including the induction of chromosomal instability, the dysregulation of oncogenic signaling pathways (specifically NF-κB), and the promotion of cellular invasion through matrix remodeling (Direct, High; PMID: 34331103).

Tumorigenic Mechanisms: Aneuploidy and Mitotic Defects

Nup88 overexpression is a potent driver of aneuploidy and chromosomal instability (CIN), which are central to tumor initiation (Direct, High; PMID: 26731471).
* Sequestration of Nup98-Rae1: Overexpressed Nup88 accumulates in the cytoplasm, where it sequesters the Nup98-Rae1 subcomplex away from the anaphase-promoting complex/cyclosome (APC/C). This prevents Nup98-Rae1 from inhibiting the premitotic activity of $APC/C^{Cdh1}$ (Direct, High; PMID: 26731471).
* Premitotic Degradation of PLK1: The resulting premature activation of $APC/C^{Cdh1}$ triggers the proteolysis of Polo-like kinase 1 (PLK1), a critical mitotic kinase and tumor suppressor. Low premitotic PLK1 levels disrupt centrosome separation, leading to asymmetrical spindles, lagging chromosomes, and chromatin bridges during anaphase (Direct, High; PMID: 26731471).
* Multinucleation: Alterations in Nup88 expression levels (both overexpression and depletion) disrupt the interaction with Nup214, leading to the formation of multipolar spindles and multinucleated cells (Direct, High; PMID: 20497554).

Oncogenic Signaling: The Nup88/Nup62/NF-κB Axis

Nup88 regulates the activity and localization of the NF-κB (p65) transcription factor, a key mediator of proliferation and anti-apoptosis in cancer (Direct, High; PMID: 36845732).
* Stabilization via Nup62: In head and neck cancers, Nup88 is co-overexpressed with Nup62. Nup62 interacts with the C-terminal region of Nup88, protecting it from ubiquitin-mediated proteasomal degradation (Direct, High; PMID: 36845732).
* Nuclear Sequestration of NF-κB: Stabilized Nup88 interact with the p65 subunit of NF-κB, sequestering active p65 in the nucleus. This constitutive activation promotes the transcription of target genes such as IL-6, c-myc, Bcl-2, and Ki-67, driving tumorigenic growth and inflammation (Direct, High; PMID: 36845732).

Unverified Citations

The following sources failed to support their assigned claims after 3 verification rounds designed to ensure only high-confidence, relevant references are retained:

• PMID:19577736 — Its overexpression is a hallmarks of various human malignancies, where it functions through distinct mechanisms includin...
  Failed: conclusion — This paper is a review that mentions Nup88 overexpression in malignancies and its possible link to NF-κB, but it does not document or establish the 'promotion of cellular invasion through matrix remodeling' as a mechanism for Nup88.
• PMID:26731471 — Its overexpression is a hallmarks of various human malignancies, where it functions through distinct mechanisms includin...
  Failed: conclusion — This paper establishes the induction of chromosomal instability but does not address matrix remodeling or the specific NF-κB dysregulation mentioned in the claim.