Bcl-xL: A Focus on Melanoma Pathobiology
Abstract
:1. Introduction
2. Melanoma
3. Bcl-2 Family
3.1. Bcl-xL: The Pro-Survival Member of the Bcl-2 Family
3.2. Regulation of Bcl-xL
- i.
- Heterogeneous nuclear ribonucleoproteins (hnRNP) that are a large family of RNA binding proteins (RBPs) that control multiple processes in RNA metabolism and whose function depends on their ability to bind the RNA and their localization. Six different hnRNP regulating BCL2L1 splicing have been identified. Among them, four have been reported to promote the production of Bcl-xS and two the production of Bcl-xL [75].
- ii.
- The serine/arginine-rich (SR) protein family that is a group of RBPs that contains a characteristic C-terminal arginine and serine-rich domain (RS domain) and one or two N-terminal RNA recognition motifs (RRMs) [76]. Different SR proteins have been identified as a key regulator in the splicing of BCL2L1. The most important of these proteins is the SRF10, which is involved in DNA damage, apoptosis, DNA repair and it has been shown to promote Bcl-xS production [77].
- iii.
- Signal transduction and activation of RNA (STAR) proteins, which constitute a family with a conserved K homology-domain and a STAR domain, responsible for the RNA recognition [78,79]. The STAR proteins can regulate the metabolism of the RNA, including the splicing. To date, the only STAR protein involved in the regulation of BCL2L1 splicing is SAM68, that when overexpressed is able to increment the isoform Bcl-xS, whilst when depleted induces an accumulation of Bcl-xL [80].
- iv.
- The RNA binding proteins, which possess the RRMs [81]. Within this group of proteins, the RBM25 has been shown to specifically interact with a sequence in exon 2 of BCL2L1 promoting the pro-apoptotic Bcl-xS 5′ splice site selection [82], while RBM11 plays an important role in the regulation of alternative splicing for neuron and germ cell differentiation [81]. RBM4 performs important functions in the inhibition of tumor progression. Specifically, it induces cancer cell apoptosis by modulating BCL2L1 splicing and shifting to the pro-apoptotic Bcl-xS isoform. Additionally, RBM4 can also antagonize the oncogenic SR protein SRSF1 to regulate BCL2L1 splicing and inhibit cancer cell growth [83].
3.3. Bcl-xL Expression and Canonical Functions in Melanoma
3.4. Non-Canonical Functions of Bcl-xL in Melanoma
4. Preclinical Studies of Bcl-xL Specific Inhibitors on Melanoma
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Lucianò, A.M.; Pérez-Oliva, A.B.; Mulero, V.; Del Bufalo, D. Bcl-xL: A Focus on Melanoma Pathobiology. Int. J. Mol. Sci. 2021, 22, 2777. https://doi.org/10.3390/ijms22052777
Lucianò AM, Pérez-Oliva AB, Mulero V, Del Bufalo D. Bcl-xL: A Focus on Melanoma Pathobiology. International Journal of Molecular Sciences. 2021; 22(5):2777. https://doi.org/10.3390/ijms22052777
Chicago/Turabian StyleLucianò, Anna Maria, Ana B. Pérez-Oliva, Victoriano Mulero, and Donatella Del Bufalo. 2021. "Bcl-xL: A Focus on Melanoma Pathobiology" International Journal of Molecular Sciences 22, no. 5: 2777. https://doi.org/10.3390/ijms22052777