NOXA

Noxa, also known as PMAIP1 (p53 up-regulated modulator of apoptosis 1), is a pro-apoptotic protein of the Bcl-2 family. It belongs to the BH3-only subset that promotes programmed cell death in response to cellular stress. The human PMAIP1 gene encodes the NOXA protein, and orthologs are found in other vertebrates.

NOXA functions by tipping the balance of Bcl-2 family proteins toward apoptosis at the mitochondrion. After upregulation, NOXA binds to anti-apoptotic proteins such as MCL-1 and BCL-XL, neutralizing their restraint on pro-apoptotic effectors. This interaction facilitates the activation of Bax and Bak, leading to mitochondrial outer membrane permeabilization, cytochrome c release, and activation of caspases that execute cell death.

Regulation of NOXA is tightly controlled. It is primarily induced transcriptionally in response to cellular stress via the p53 tumor suppressor pathway, particularly after DNA damage. Other stress pathways can contribute to its expression, including ER stress through CHOP-mediated transcription. NOXA is typically a short‑lived protein whose levels are governed by ubiquitin-proteasome–mediated degradation, allowing rapid modulation of apoptotic signaling.

Expression of NOXA is widespread but context-dependent, with relevance to cancer biology. In many tumors, NOXA induction can enhance sensitivity to chemotherapy by promoting apoptosis, whereas resistance can arise from high levels of MCL-1 or loss of p53 function. As a result, NOXA is a focus of research into therapeutic strategies that modulate BH3-only proteins and anti-apoptotic Bcl-2 family members.

In summary, NOXA is a p53-regulated, mitochondria-associated pro-apoptotic factor that contributes to stress-induced cell death by antagonizing anti-apoptotic Bcl-2 proteins.