# MCL1

## Overview
The MCL1 gene encodes the MCL1 apoptosis regulator, a protein that is a critical member of the BCL2 family, known for its role in regulating apoptosis and cell survival. This protein is characterized by its anti-apoptotic function, primarily through its ability to bind and sequester pro-apoptotic proteins, thereby preventing cell death. MCL1 is integral to mitochondrial homeostasis and is involved in various cellular processes, including cell cycle regulation and mitophagy. The gene is essential for normal embryonic development and hematopoiesis, with its expression being tightly regulated to maintain cellular balance. Dysregulation of MCL1 is implicated in several pathological conditions, notably in cancer, where its overexpression is associated with tumor survival and resistance to therapy. The protein's complex structure, featuring multiple Bcl-2 homology domains and a transmembrane domain, facilitates its diverse interactions and functional versatility (Mittal2021Myeloid; Senichkin2019Molecular; Sancho2021Understanding).

## Structure
The MCL1 protein, a member of the BCL2 family, is characterized by its complex molecular structure, which plays a crucial role in its function as an apoptosis regulator. The primary structure of MCL1 includes several Bcl-2 homology (BH) domains: BH1, BH2, BH3, and BH4, along with a transmembrane (TM) domain at the C-terminal (Mittal2021Myeloid; Akgul2000Functional). The BH3 domain is particularly important for its anti-apoptotic function, as it facilitates interactions with pro-apoptotic proteins (Bingle2000Exon).

The secondary structure of MCL1 is composed of eight alpha helices, which contribute to its globular form (Mittal2021Myeloid). The tertiary structure features a hydrophobic groove that is essential for binding pro-apoptotic BH3-only proteins, thereby inhibiting apoptosis (Senichkin2019Molecular).

MCL1 can form both homodimers and heterodimers, indicating a quaternary structure that is significant for its function in apoptosis regulation (Mittal2021Myeloid). The protein undergoes post-translational modifications such as phosphorylation and ubiquitination, which affect its stability and degradation (Mittal2021Myeloid).

MCL1 exists in multiple splice variant isoforms, including the anti-apoptotic MCL-1L and the pro-apoptotic MCL-1S and MCL-1ES, which result from alternative splicing and influence its role in apoptosis (Mittal2021Myeloid; Senichkin2019Molecular).

## Function
The MCL1 gene encodes a protein that is a member of the BCL2 family, playing a crucial role in regulating apoptosis and cell cycle progression in healthy human cells. MCL1 functions as an anti-apoptotic protein by sequestering pro-apoptotic factors such as Bim, tBid, Puma, and Noxa, thereby preventing cell death (Senichkin2019Molecular). It is involved in mitochondrial homeostasis, where it modulates mitochondrial outer membrane permeabilization, a key step in the apoptotic pathway (Sancho2021Understanding). MCL1 also interacts with proteins like LC3A to promote mitophagy, maintaining mitochondrial function and energy balance (Sancho2021Understanding).

In terms of cell cycle regulation, MCL1 interacts with proliferating cell nuclear antigen (PCNA) to inhibit cell cycle progression through the S-phase, a process distinct from its anti-apoptotic function (Fujise2000Regulation). This interaction is unique among BCL2 family proteins and highlights MCL1's dual role in apoptosis inhibition and cell cycle regulation (Fujise2000Regulation).

MCL1 is also essential for embryonic development, particularly in neural precursor cell survival and thymocyte differentiation, and is highly expressed in long-term hematopoietic stem cells, indicating its role in early hematopoiesis (Sancho2021Understanding).

## Clinical Significance
The MCL1 gene, a member of the BCL2 family, plays a significant role in cancer biology due to its involvement in apoptosis regulation. Overexpression of MCL1 is frequently observed in various cancers, including acute myeloid leukemia, breast cancer, non-small cell lung cancer, and hepatocellular carcinoma, where it contributes to oncogenesis by inhibiting apoptosis and promoting cell survival (Senichkin2020Saga; Mittal2021Myeloid). This overexpression is often linked to poor prognosis and resistance to anticancer therapies, such as venetoclax in acute myeloid leukemia (Tantawy2023Targeting; Senichkin2020Saga).

In lung adenocarcinoma, MCL1 is frequently amplified, leading to increased mRNA and protein levels, which are associated with tumor survival and resistance to therapies (Munkhbaatar2020MCL1). Targeting MCL1 with specific inhibitors has shown potential in reducing tumor growth and overcoming drug resistance (Munkhbaatar2020MCL1).

MCL1 dysregulation is also implicated in heart disease, where its deletion in cardiac tissue results in severe cardiac dysfunction and mitochondrial abnormalities, highlighting potential cardiac toxicity concerns for MCL1-targeted cancer therapies (Wang2013Deletion). In chronic liver disease, MCL1 depletion increases apoptosis and fibrosis, potentially promoting cancer development (Sancho2021Understanding).

## Interactions
MCL1, a member of the Bcl-2 family, is involved in various protein-protein interactions that regulate apoptosis and cell survival. It interacts with the tumor suppressor protein p73, binding to the reverse BH3 (rBH3) motif in p73's transactivation domain. This interaction inhibits p73's ability to bind DNA, thereby suppressing its transcriptional activity and affecting its role in DNA damage response and apoptosis (Widden2020MCL1). MCL1 can bind to all native isoforms of p73, including TAp73α, ΔNp73α, and TAp73β, as demonstrated in cell culture models (Widden2020MCL1).

MCL1 also interacts with cyclin-dependent kinase 1 (Cdk1), where its overexpression leads to decreased Cdk1 activity. This interaction affects cell growth by altering the binding of Cdk1 to its partner cyclins, such as cyclin B1, without changing the Cdk1 protein levels (JAMIL2005A).

Additionally, MCL1 binds to BH3-only proteins like Noxa, Puma, and Bim. These interactions are crucial for its anti-apoptotic function, as they inhibit the pro-apoptotic activity of these proteins. The binding specificity involves conserved hydrophobic residues and a conserved aspartic acid in the BH3-only proteins (Fogha2017Toward; Dutta2010Determinants).


## References


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[2. (Sancho2021Understanding) Mónica Sancho, Diego Leiva, Estefanía Lucendo, and Mar Orzáez. Understanding mcl1: from cellular function and regulation to pharmacological inhibition. The FEBS Journal, 289(20):6209–6234, August 2021. URL: http://dx.doi.org/10.1111/febs.16136, doi:10.1111/febs.16136. This article has 30 citations.](https://doi.org/10.1111/febs.16136)

[3. (JAMIL2005A) Sarwat JAMIL, Rafat SOBOUTI, Payman HOJABRPOUR, Meera RAJ, Juergen KAST, and Vincent DURONIO. A proteolytic fragment of mcl-1 exhibits nuclear localization and regulates cell growth by interaction with cdk1. Biochemical Journal, 387(3):659–667, April 2005. URL: http://dx.doi.org/10.1042/bj20041596, doi:10.1042/bj20041596. This article has 63 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1042/bj20041596)

[4. (Senichkin2019Molecular) Viacheslav V. Senichkin, Alena Y. Streletskaia, Boris Zhivotovsky, and Gelina S. Kopeina. Molecular comprehension of mcl-1: from gene structure to cancer therapy. Trends in Cell Biology, 29(7):549–562, July 2019. URL: http://dx.doi.org/10.1016/j.tcb.2019.03.004, doi:10.1016/j.tcb.2019.03.004. This article has 63 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.tcb.2019.03.004)

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[11. (Munkhbaatar2020MCL1) Enkhtsetseg Munkhbaatar, Michelle Dietzen, Deepti Agrawal, Martina Anton, Moritz Jesinghaus, Melanie Boxberg, Nicole Pfarr, Pidassa Bidola, Sebastian Uhrig, Ulrike Höckendorf, Anna-Lena Meinhardt, Adam Wahida, Irina Heid, Rickmer Braren, Ritu Mishra, Arne Warth, Thomas Muley, Patrina S. P. Poh, Xin Wang, Stefan Fröhling, Katja Steiger, Julia Slotta-Huspenina, Martijn van Griensven, Franz Pfeiffer, Sebastian Lange, Roland Rad, Magda Spella, Georgios T. Stathopoulos, Jürgen Ruland, Florian Bassermann, Wilko Weichert, Andreas Strasser, Caterina Branca, Mathias Heikenwalder, Charles Swanton, Nicholas McGranahan, and Philipp J. Jost. Mcl-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically. Nature Communications, September 2020. URL: http://dx.doi.org/10.1038/s41467-020-18372-1, doi:10.1038/s41467-020-18372-1. This article has 34 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-020-18372-1)

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[13. (Bingle2000Exon) Colin D. Bingle, Ruth W. Craig, Brenka M. Swales, Vanessa Singleton, Ping Zhou, and Moira K.B. Whyte. Exon skipping in mcl-1 results in a bcl-2 homology domain 3 only gene product that promotes cell death. Journal of Biological Chemistry, 275(29):22136–22146, July 2000. URL: http://dx.doi.org/10.1074/jbc.m909572199, doi:10.1074/jbc.m909572199. This article has 151 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m909572199)

[14. (Mittal2021Myeloid) Pooja Mittal, Sujata Singh, Rajesh Sinha, Anju Shrivastava, Archana Singh, and Indrakant Kumar Singh. Myeloid cell leukemia 1 (mcl-1): structural characteristics and application in cancer therapy. International Journal of Biological Macromolecules, 187:999–1018, September 2021. URL: http://dx.doi.org/10.1016/j.ijbiomac.2021.07.166, doi:10.1016/j.ijbiomac.2021.07.166. This article has 20 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ijbiomac.2021.07.166)