BTF3

BTF3
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	3LKX, 3MCB
Identifiers
Aliases	BTF3, BETA-NAC, BTF3a, BTF3b, NACB, basic transcription factor 3
External IDs	OMIM: 602542; MGI: 1202875; HomoloGene: 37453; GeneCards: BTF3; OMA:BTF3 - orthologs
Gene location (Human)
Chr.	Chromosome 5 (human)
End	73,505,667 bp
Gene location (Mouse)
Chr.	Chromosome 13 (mouse)
End	98,453,514 bp
RNA expression pattern
	Top expressed in
	mucosa of sigmoid colon; ; lactiferous duct; ; human penis; ; left ovary; ; embryo; ; vulva; ; ganglionic eminence; ; oral cavity; ; trabecular bone; ; cartilage tissue;
	Top expressed in
	epiblast; ; lens; ; ventricular zone; ; ganglionic eminence; ; yolk sac; ; embryo; ; embryo; ; thymus; ; blastocyst; ; uterus;
	More reference expression data
	n/a
Gene ontology
Molecular function	protein binding; RNA binding;
Cellular component	cytoplasm; nucleus; cytosol; nascent polypeptide-associated complex; polysomal ribosome;
Biological process	protein transport; in utero embryonic development; regulation of transcription, DNA-templated; transcription by RNA polymerase II; transcription, DNA-templated; transport;
	Sources:Amigo / QuickGO
Orthologs
	689
	218490
	ENSG00000145741
	ENSMUSG00000021660
	P20290
	Q64152
	NM_001207; NM_001037637; NM_001393652; NM_001393653
	NM_001170540; NM_145455
	NP_001032726; NP_001198
	NP_001164011; NP_663430
	Wikidata
View/Edit Human	View/Edit Mouse

Basic transcription factor 3 is a eukaryotic protein that in humans is encoded by the BTF3 gene. They are very important to the development of many eukaryotic organisms such as in humans, plants, fungi, and protists. Some of the functions it plays a part in are gene expression regulation, cell proliferation control, protein homeostasis maintenance, and stress response modulation. BTF3 can be produced in both transcriptionally active and transcriptionally inactive forms through alternative splicing. This helps it to work in multiple cellular compartments and regulatory pathways.^[5]

BTF3 evolutionary conservation shows how important its involvement in gene control and cellular homeostasis is. Overtime, it's known for its role in cancer progression and metastasis. This includes gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma, and nasopharyngeal carcinoma.^[5]

More current studies has enhanced our understanding of BTF3 beyond its original designation as a generic transcription factor. Early biochemical studies indicated that BTF3 forms a stable, functional complex with RNA polymerase II, which is required for proper promoter binding and transcription initiation.^[6] BTF3 is the β-subunit of the Nascent Polypeptide-Associated Complex (NAC). It attaches to ribosomes at the nascent polypeptide exit tunnel, preventing premature interactions and protein misfolding. This establishes BTF3 as a key regulator of co-translational protein quality regulation.^[7]

Properties

Structure

BTF3 is a compact α-helical protein of about 180-210 amino acids, which depend on the isoform produced.^[8] The protein has a three-dimensional structure and can be roughly classified into two functional regions. The first is the N-terminal region. This has about the first 90 amino acids and is responsible for BTF3's traditional classification as a transcription factor. Using cDNA sequencing and biochemical research, it was shown that BTF3 is needed for promoter binding and contributes to the development of the pre-initiation complex. The second is BTF3's C-terminal region, this has the β-NAC domain. It's an important structural and functional component of the Nascent Polypeptide-Associated Complex and it ranges from 90-200. The NAC complex binds to ribosomes near the polypeptide exit tunnel, which prevents fold error and promotes correct nascent-chain targeting.^[7]

In humans, there are two major isoforms, which are BTF3a and BTFb. The BTF3a is the longer protein that is transcriptionally active, while the BTFb is the shortened one that is transcriptionally inactive.^[5]^[6]

Composition

BTF3's amino acid composition is has α-helical residues. In humans, BTF3 has leucine (9.9%), alanine (9.9%), and lysine (9.9%).^[9] There's a significant concentration of basic amino acids, lysine and arginine, especially in the N-terminal region. It allows interactions with DNA, transcriptional cofactors, and the acidic surfaces of the transcription machinery.

The C-terminal NAC region has hydrophobic and aromatic residues that are important for ribosome docking and stabilizing interactions with α-NAC. Post-translational changes to the protein affect its nuclear place as well as its interaction with partner proteins and having these changes likely affects the BTF3's actions.^[10]

Solubility

BTF3 is a soluble, α-helical protein that is stable under physiological buffer conditions. Its solubility was first shown during early purification operations, when BTF3 was successfully identified as a soluble transcription factor that remains in solution while building complexes with RNA polymerase II.^[11] A structural and biochemical investigation on NAC found that the β-NAC subunit is soluble and interacts to the ribosomal exit tunnel to avoid protein folding errors.^[9]

The ribosome-associated β-NAC component inhibits nascent chain targeting errors and remains soluble in physiological buffer conditions, contributing to the stability of NAC complexes, including BTF3's high solubility.^[12] BTF3 is a cytosolic/nuclear, soluble protein that lacks transmembrane helices and is distributed similarly to freely soluble transcription and chaperone proteins.

Biological role

BTF3 has many important activities in eukaryotic cells, such as transcription, translation, and cellular growth regulation. Its most fundamental biological role was discovered in 1987 that showed that BTF3 forms a stable complex with RNA polymerase II and is important for proper transcription initiation. This meant that it helped in facilitating both the construction of the pre-initiation complex and the shift to early elongation. This discovery confirmed BTF3 as a fundamental universal transcription factor and gave the first molecular understanding of how BTF3 regulates gene expression at the promoter level.^[8]

The structural and biochemical investigations that has been done showed that β-NAC forms a stable heterodimer with α-NAC and dynamically associates with translating ribosomes to regulate protein maturation. So, in this function BTF3 connects transcriptional regulation to translational quality assurance. This works both upstream and downstream in gene expression pathways. This means that BTF3 also plays an important role in cell proliferation and cancer biology.^{[citation needed]}

BTF3 affects the expression of cell cycle elated genes, for example the FOXM1, Ki-67, PCNA, and P27. When BTF3 was suppressed in gastric cancer cells, it lowered proliferation, delayed S- and G2/M-phases. It also increased apoptosis, and inhibited epithelial-mesenchymal transition (EMT). BTF3 increases EMT and metastatic potential by increasing the JAK2 or STAT3 signaling pathways. Having FOXM1, eliminates several of these cancer-related issues. This shows that BTF3 is a critical upstream regulator of this cancer-causing transcription factor. It supports normal cellular functions as well as contributes to pathogenic processes.^[7]

This demonstrates its importance in coordinating gene expression with cell development and survival. BTF3's significance in both essential biological processes and disease pathways explains why it exists in eukaryotic cells. Overall, it demonstrates how alterations in its expression can cause important developmental or pathological outcomes.

Interactions

BTF3 has been shown to interact with CSNK2B.^[13]

BTF3 had been shown to interact is BMI1. Most recently it shows that it sustains prostate cancer stemness.^[14]

BTF3 directly interacts with FOXM1, this promotes proliferation and glycolysis in hepatocellular carcinoma (HCC) cells.^[15]

BTF3 binds to the PDCD2L promoter and stimulates transcription in hepatocellular cancer. BTF3 binds to the PDCD2L proximal promoter and increases transcription, connecting BTF3 to a significant proliferation and apoptosis regulating mechanism in liver cancer.^[16]

BTF3 functionally interacts with p53-associated signaling via PDCD2L. By raising PDCD2L, BTF3 indirectly suppresses p53 pathway activity, lowering p53, p21, and Bax levels while increasing Bcl-2. This puts BTF3 in an important position in balancing survival and death.^[16]

BTF3 controls the JAK2/STAT3 signaling pathway, which controls cell migration, invasion, and EMT. Loss of BTF3 lowers JAK2 and STAT3 phosphorylation, but IL-6 stimulation restores pathway activity and rescues EMT markers, showing that BTF3 maintains STAT3-driven metastatic behaviors.^[17]

Regulations

BTF3 regulates important cell-cycle regulators through the FOXM1 pathway.^[17] In gastric cancer, BTF3 regulates FOXM1 gene expression, which then regulates Ki-67, PCNA, and p27. BTF3 loss causes stunted growth and death, but FOXM1 production rescues these deficiencies.^[16]
Regulation of PDCD2L and the p53 pathway^[16] BTF3 increases PDCD2L, which inhibits the p53 axis. When BTF3 or PDCD2L are suppressed, p53, p21, and Bax rise, while Bcl-2 falls. This restores pro-apoptotic signaling. This identifies BTF3 as a key regulator of p53-dependent stress and survival pathways.^[16]
BTF3 regulates the JAK2/STAT3 signaling axis, which controls EMT and metastatic behavior.^[16] When BTF3 is silenced, JAK2 and STAT3s break down. This results in decreased EMT and impaired migration. Yet, IL-6 stimulation can restore STAT3 activation, proving that BTF3 modulates EMT states through cytokine-responsive signaling pathways.
BTF3 regulates EMT-related transcriptional states.^[16]
In hepatocellular carcinoma, BTF3 transcriptionally promotes PDCD2L, which influences p53 signaling.^[16]
BTF3 increases transcriptional initiation by participating in the general TFII machinery
Coordination of transcription and translation: BTF3 regulates both promoter-level transcription and ribosome-associated protein maturation, helping it to integrate upstream gene expression with downstream proteostasis.^[6]
Regulation of apoptosis and cell-cycle transitions: BTF3 regulates transitions through S and G2/M phases in cancer cells by acting on PDCD2L, FOXM1, and downstream p53 signaling. It also affects proliferation marker expression and defines apoptotic thresholds.^[16]^[17]
Regulation of invasion and migration^[16] BTF3 knockdown reduces invasive and migratory threat by modifying EMT-related transcriptional outputs, such as enhanced E-cadherin and decreased N-cadherin and ZEB2.

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000145741 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000021660 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b ^c "Gene - BTF3". maayanlab.cloud. Retrieved 2025-12-02.
^ ^a ^b ^c Jamil M, Wang W, Xu M, Tu J (2015-07-03). "Exploring the roles of basal transcription factor 3 in eukaryotic growth and development". Biotechnology & Genetic Engineering Reviews. 31 (1–2): 21–45. doi:10.1080/02648725.2015.1080064. PMID 26428578.
^ ^a ^b ^c Freire MA (January 2005). "Translation initiation factor (iso) 4E interacts with BTF3, the beta subunit of the nascent polypeptide-associated complex". Gene. 345 (2): 271–277. doi:10.1016/j.gene.2004.11.030. PMID 15716105.
^ ^a ^b Zheng XM, Black D, Chambon P, Egly JM (April 1990). "Sequencing and expression of complementary DNA for the general transcription factor BTF3". Nature. 344 (6266): 556–559. Bibcode:1990Natur.344..556Z. doi:10.1038/344556a0. PMID 2320128. S2CID 4227320.
^ ^a ^b "UniProt". UniProt. Retrieved 2025-12-02.
^ "BTF3 basic transcription factor 3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2025-12-02.
^ Wiedmann B, Sakai H, Davis TA, Wiedmann M (August 1994). "A protein complex required for signal-sequence-specific sorting and translocation". Nature. 370 (6489): 434–440. Bibcode:1994Natur.370..434W. doi:10.1038/370434a0. PMID 8047162.
^ "Entrez Gene: BTF3 basic transcription factor 3".
^ Grein S, Pyerin W (January 1999). "BTF3 is a potential new substrate of protein kinase CK2". Molecular and Cellular Biochemistry. 191 (1–2): 121–128. doi:10.1023/A:1006806226764. PMID 10094400. S2CID 1057554.
^ Zhang Y, Gao X, Yi J, Sang X, Dai Z, Tao Z, et al. (January 2021). "BTF3 confers oncogenic activity in prostate cancer through transcriptional upregulation of Replication Factor C". Cell Death & Disease. 12 (1) 12. doi:10.1038/s41419-020-03348-2. PMC 7791038. PMID 33414468.
^ Wang P, Sun J, Sun C, Zhao H, Zhang Y, Chen J (December 2023). "BTF3 promotes proliferation and glycolysis in hepatocellular carcinoma by regulating GLUT1". Cancer Biology & Therapy. 24 (1) 2225884. doi:10.1080/15384047.2023.2225884. PMC 10312033. PMID 37382415.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Kong M, Shi X, Gao J, Guo W (December 2024). "BTF3 affects hepatocellular carcinoma progression by transcriptionally upregulating PDCD2L and inactivating p53 signaling". Molecular Medicine. 30 (1) 252. doi:10.1186/s10020-024-01044-x. PMC 11660624. PMID 39707202.
^ ^a ^b ^c Zhang DZ, Chen BH, Zhang LF, Cheng MK, Fang XJ, Wu XJ (November 2017). "Basic Transcription Factor 3 Is Required for Proliferation and Epithelial-Mesenchymal Transition via Regulation of FOXM1 and JAK2/STAT3 Signaling in Gastric Cancer". Oncology Research. 25 (9): 1453–1462. doi:10.3727/096504017X14886494526344. PMC 7841179. PMID 28276310.

External links

Human BTF3 genome location and BTF3 gene details page in the UCSC Genome Browser.
PDBe-KB provides an overview of all the structure information available in the PDB for Human Transcription factor BTF3