C-Terminal Binding Protein: Regulator between Viral Infection and Tumorigenesis

Abstract

C-terminal binding protein (CtBP), a transcriptional co-repressor, significantly influences cellular signaling, impacting various biological processes including cell proliferation, differentiation, apoptosis, and immune responses. The CtBP family comprises two highly conserved proteins, CtBP1 and CtBP2, which have been shown to play critical roles in both tumorigenesis and the regulation of viral infections. Elevated CtBP expression is noted in various tumor tissues, promoting tumorigenesis, invasiveness, and metastasis through multiple pathways. Additionally, CtBP's role in viral infections varies, exhibiting differing or even opposing effects depending on the virus. This review synthesizes the advances in CtBP's function research in viral infections and virus-associated tumorigenesis, offering new insights into potential antiviral and anticancer strategies.

Keywords: C-terminal binding protein (CtBP); corepressor; transcriptional coregulator; tumorigenesis; viral infection.

Figure 1

Two types of CtBP and their possible biological roles. CtBP, C-terminal binding protein; p16INK4A, a tumor suppressor protein; INK4A/Arf, Inhibitor of Cyclin-Dependent Kinase 4/alternative reading frame; HIPK2, Homeodomain interacting protein kinase 2; APC, Adenomatous polyposis coli; PXDLS, Pro-X-Asp-Leu-Ser (PXDLS) motif; HDAC, Histone deacetylases; HPC2, Human Polycomb Protein 2; CtIP, CtBP-interacting protein. The CtBP family includes two crucial proteins, CtBP1/CtBP2. CtBP acts as a negative regulator of tumor suppressors p16INK4A, INK4A/Arf, APC, and HIPK2, leading to cell apoptosis. CtBP proteins can exert their functions by recognizing the PXDLS motif within DNA-binding proteins. As for non-PXDLS-containing proteins, CtBP proteins interact with HDAC, HPC2, and CtIP. These interactions ultimately lead to the repression of gene transcription associated with embryonic development, cell differentiation, and tumorigenesis.

Figure 2

Interaction of CtBP with adenovirus and its role in tumor transformation and viral replication. CtBP, C-terminal binding protein; CR, conserved region; Ras, rat sarcoma; pRB, retinoblastoma; p300/CBP, transcriptional regulators; NADH, nicotinamide adenine dinucleotide; PLDLS motif, Pro-Leu-Asp-Leu-Ser. The adenovirus-expressed E1A protein consists of 289 amino acid residues, of which amino acids 1 to 186 are encoded by exon 1 and amino acids 187 to 289 are encoded by exon 2. On the one hand, transcriptional regulators such as Ras, pRb, and p300/CBP can enhance the tumorigenic-promoting effect of exon 1. On the other hand, exon 2 can inhibit the upstream pathway of exon 1 action, inhibiting cellular immortalization and tumorigenesis, and at the same time, exon 2 also has the biological activity of promoting adenovirus replication. CtBP, as a transcriptional co-repressor protein, can interact with the C-terminal region of the adenovirus E1A protein through the PLDLS motif. During viral infection, intracellular levels of NADH recruit CtBP to affect the activity of the E1A protein and enhance the interaction of CtBP with the E1A protein.