BCL3

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Template:Cs1 config Template:Short description Script error: No such module "For". An Error has occurred retrieving Wikidata item for infobox B-cell lymphoma 3-encoded protein is a protein that in humans is encoded by the BCL3 gene.[1][2]

This gene is a proto-oncogene candidate. It is identified by its translocation into the immunoglobulin alpha-locus in some cases of B-cell leukemia. The protein encoded by this gene contains seven ankyrin repeats, which are most closely related to those found in I kappa B proteins. This protein functions as a transcriptional coactivator that activates through its association with NF-kappa B homodimers. The expression of this gene can be induced by NF-kappa B, which forms a part of the autoregulatory loop that controls the nuclear residence of p50 NF-kappa B.[3]

Like BCL2, BCL5, BCL6, BCL7A, BCL9, and BCL10, it has clinical significance in lymphoma.

Interactions

BCL3 has been shown to interact with:

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Clinical significance

Genetic variations in BCL3 gene have been associated with late-onset Alzheimer's disease (LOAD) and chronic lymphocytic leukemia. β-amyloid accumulation in neurons of Alzheimer's patients results in activation of NF-κB, which induces BCL3 expression.[12] Increased expression of BCL3 has been observed in the brains of patients with LOAD.[13]

The role of Bcl3 in solid tumors was established through the ability of Bcl3 to promote metastasis without affecting primary tumor growth or normal mammary function, within models of ErbB2-positive breast cancer.[14] Further research has uncovered the role of Bcl3 in promoting progression of other solid tumors. The role of Bcl3 in promoting tumor hallmarks has been most widely reported for advanced colorectal cancer; where Bcl3 expression is up-regulated in >30% of colorectal cancer cases and is associated with a poor prognosis. For example, in colorectal cancer models, elevated Bcl3 expression was found to activate AKT signalling,[15] drive a cancer stem cell phenotype through enhancing β-catenin signalling,[16] drive the COX-2 mediated response to inflammatory cytokines,[17] and protect colorectal tumor cells against DNA damage.[18] The role of Bcl3 in enabling multiple cancer hallmarks in colorectal carcinogenesis has been reviewed.[19]

More recently other cancer cell signalling pathways have been shown to be modulated by Bcl3. These include Wnt/beta-catenin through direct protein interaction;[16] Smad3, through an unknown mechanism of protein stabilisation[20] and transcriptional regulation of Stat3.[21][22] Other pathways influenced by Bcl3 activity include phosphorylation of AKT through an unknown mechanism.[15]

Role in cancer therapy

Bcl3 also influences responses of cancer cells to treatment. Bcl3 promotes resistance to alkylating chemotherapy in gliomas,[23] DNA damaging agents in colorectal cancer,[18] and regulates the cancer immune checkpoint control gene PD-L1 in ovarian cancer cells.[24]

The first discovery of a small molecule anti-metastatic Bcl3 inhibitor was reported utilising a virtual drug design and screening approach, targeting the protein-protein interaction between Bcl3 and partner protein p50.[25] The virtual screening hit compound showed potent intracellular Bcl3-inhibitory activity, and led to reductions in NF-κB signalling, tumor colony formation and cancer cell migration within in vitro cellular models of breast cancer. In vivo inhibition of tumor growth and anti-metastatic activity was observed in invasive breast cancer models, without overt systemic toxicity.

Development

TNA Therapeutics, is the only company engaged in developing a BCL3 inhibitor. TNAT-101, is an orally bioavailable, small molecule inhibitor of the novel target BCL3. BCL3 is a transcriptional regulator of multiple pathways critical for cancer initiation, maintenance and progression. It plays an important role in tumor growth, cell death, migration, metastasis and cancer stem cell viability.

https://www.tnatherapeutics.com/

References

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  1. ^ Page Module:Citation/CS1/styles.css has no content.Wulczyn FG, Naumann M, Scheidereit C (August 1992). "Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-kappa B". Nature. 358 (6387): 597–599. Bibcode:1992Natur.358..597W. doi:10.1038/358597a0. PMID 1501714. S2CID 4363340.
  2. ^ Page Module:Citation/CS1/styles.css has no content.Ohno H, Takimoto G, McKeithan TW (March 1990). "The candidate proto-oncogene bcl-3 is related to genes implicated in cell lineage determination and cell cycle control". Cell. 60 (6): 991–997. doi:10.1016/0092-8674(90)90347-H. PMID 2180580. S2CID 1919787.
  3. ^ Page Module:Citation/CS1/styles.css has no content."Entrez Gene: BCL3 B-cell CLL/lymphoma 3".
  4. ^ a b c d Page Module:Citation/CS1/styles.css has no content.Dechend R, Hirano F, Lehmann K, Heissmeyer V, Ansieau S, Wulczyn FG, et al. (June 1999). "The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators". Oncogene. 18 (22): 3316–3323. doi:10.1038/sj.onc.1202717. PMID 10362352. S2CID 2356435.
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  6. ^ Page Module:Citation/CS1/styles.css has no content."Molecular Interaction Database". Archived from the original on 2006-05-06. Retrieved 2012-05-08.
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  14. ^ Page Module:Citation/CS1/styles.css has no content.Wakefield A, Soukupova J, Montagne A, Ranger J, French R, Muller WJ, Clarkson RW (January 2013). "Bcl3 selectively promotes metastasis of ERBB2-driven mammary tumors". Cancer Research. 73 (2): 745–755. doi:10.1158/0008-5472.CAN-12-1321. PMID 23149915. S2CID 342425.
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Further reading

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