Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the RELA gene. RELA, also known as p65, is a REL-associated protein involved in NF-κB heterodimer formation, nuclear translocation and activation . NF-κB is an essential transcription factor complex involved in all types of cellular processes, including cellular metabolism, chemotaxis, etc. Phosphorylation and acetylation of RELA are crucial post-translational modifications required for NF-κB activation. RELA has also been shown to modulate immune responses, and activation of RELA is positively associated with multiple types of cancer. Gene and expression RELA, or v-rel avian reticuloendotheliosis viral oncogene homolog A, is also known as p65 or NFKB3. It is located on chromosome 11 q13, and its nucleotide sequence is 1473 nucleotide long. RELA protein has four isoforms, the longest and the predominant one being 551 amino acids. RELA is expressed alongside p50 in various cell types, including epithelial/endothelial cells and neuronal tissues. Structure RELA is one member of the NF-κB family, one of the essential transcription factors under intensive study. Seven proteins encoded by five genes are involved in the NF-κB complex, namely p105, p100, p50, p52, RELA, c-REL and RELB. Like other proteins in this complex, RELA contains a N-terminal REL-homology domain (RHD), and also a C-terminal transactivation domain (TAD). RHD is involved in DNA binding, dimerization and NF-κB/REL inhibitor interaction. On the other hand, TAD is responsible for interacting with the basal transcription complex including many coactivators of transcription such as TBP, TFIIB and CREB-CBP. RELA and p50 is the mostly commonly found heterodimer complex among NF-κB homodimers and heterodimers, and is the functional component participating in nuclear translocation and activation of NF-κB. RELA is a 65 kDa protein. Phosphorylation Phosphorylation of RELA plays a key role in regulating NF-κB activation and function. Subsequent to NF-κB nuclear translocation, RELA undergoes site-specific post-translational modifications to further enhance the NF-κB function as a transcription factor. RELA can either be phosphorylated in the RHD region or the TAD region, attracting different interaction partners. Triggered by lipopolysaccharide (LPS), protein kinase A (PKA) specifically phosphorylates serine 276 in the RHD domain in the cytoplasm, controlling NF-κB DNA-binding and oligomerization. On the other hand, mitogen and stress-activated kinase 1 (MSK1) are also able to phosphorylate RELA at residue 276 under TNFα induction in the nucleus, increasing NF-κB response at the transcriptional level. Phosphorylation of serine 311 by