MCL1

MCL1 Background

Myeloid cell leukemia 1, encoded by the MCL1 gene, is an anti-apoptotic member of the Bcl-2 family ^[1]. The MCL1 protein was originally identified as an immediate-early gene expressed during PMA-induced differentiation of ML-1 myeloid leukemia cells ^[2]. Like its Bcl-2 relatives, MCL1 is ubiquitously expressed but has its particular tissue distribution ^[3][4] along with its specific physiological roles. Sequence analysis revealed that MCL1 contained 3 putative BH domains and its large N-terminal region included potential regulatory motifs that could be predicted to modulate its pro-survival function. Lack of the transmembrane domain in the C-terminal region of MCL1 blocks its membrane insertion and localization ^[5]. MCL1 is capable of heterodimerizing with other Bcl-2 family members due to the high structural and functional homology between its resides 170-300 and both Bcl-2 and Bcl-Xl ^[6]. Three studies exhibited that MCL1 is structurally similar to its pro-survival relatives, with a surface surface-exposed hydrophobic groove for the binding of other BH3 domain-containing proteins ^[7-9]. Mcl-1 binds and sequesters the pro-apoptotic proteins such as Bak and Bax, thus inhibiting apoptosis. And MCL1 also associates with and obstructs a subset of the BH3-only pro-apoptotic Bcl-2 family members, which induce the polymerization of Bak and Bax. The degradation of MCL1 can attenuate the suppression of Bak and Bax polymerization. MCL1's interaction with a second subset of the BH3-only pro-apoptotic Bcl-2 family members, which induce dissociation of Bak and Bax from Mcl-1, can also achieve the aim. Numerous diverse cell-types are reliant on MCL1 for their survival and development. For instance, MCL1 deletion is peri-implantation lethal in mouse embryogenesis ^[10]. MCL1 has also been shown to be required for the development and maintenance of B and T-lymphocytes ^[11] and is also required for neural development ^[12].

[1] Craig RW, Jabs EW, et al. Human and mouse chromosomal mapping of the myeloid cell leukemia-1 gene: MCL1 maps to human chromosome 1q21, a region that is frequently altered in preneoplastic and neoplastic disease [J]. Genomics. 1995, 23 (2): 457–63.
[2] Kozopas KM, Yang T, et al. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2[J]. Proc Natl Acad Sci U S A. 1993, 90 (8): 3516–20.
[3] T. Yang, K.M. Kozopas, et al. The intracellular distribution and pattern of expression of Mcl-1 overlap with, but are not identical to, those of Bcl-2 [J]. J. Cell Biol., 128 (6) (1995), pp. 1173-1184.
[4] S. Krajewski, et al. Immunohistochemical analysis of Mcl-1 protein in human tissues. Differential regulation of Mcl-1 and Bcl-2 protein production suggests a unique role for Mcl-1 in control of programmed cell death in vivo [J]. Am. J. Pathol., 146 (6) (1995), pp. 1309-1319.
[5] C. Akgul, et al. In vivo localisation and stability of human Mcl-1 using green fluorescent protein (GFP) fusion proteins [J]. FEBS Lett., 478 (1–2) (2000), pp. 72-76.
[6] R.J. Lutz. Role of the BH3 (Bcl-2 homology 3) domain in the regulation of apoptosis and Bcl-2-related proteins [J]. Biochem. Soc. Trans., 28 (2) (2000), pp. 51-56.
[7] C.L. Day, et al. Solution structure of prosurvival Mcl-1 and characterization of its binding by proapoptotic BH3-only ligands [J]. J. Biol. Chem., 280 (6) (2005), pp. 4738-4744.
[8] L. Chen, et al. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function [J]. Mol. Cell, 17 (3) (2005), pp. 393-403.
[9] C.L. Day, et al. Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1 [J]. J. Mol. Biol., 380 (5) (2008), pp. 958-971.
[10] J.L. Rinkenberger, et al. Mcl-1 deficiency results in peri-implantation embryonic lethality [J]. Genes Dev., 14 (1) (2000), pp. 23-27.
[11] J.T. Opferman, et al. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1 [J]. Nature, 426 (6967) (2003), pp. 671-676.
[12] N. Arbour, et al. Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage [J]. J. Neurosci., 28 (24) (2008), pp. 6068-6078.