AUTHOR=Chin Hui San , Fu Nai Yang 

TITLE=Physiological Functions of Mcl-1: Insights From Genetic Mouse Models

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 9 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.704547

DOI=10.3389/fcell.2021.704547

ISSN=2296-634X

ABSTRACT=Proteins of the Bcl-2 family is characterized by the presence of at least one of the four Bcl-2 homology
(BH) domains. In mammals, this protein family consists of BH3-only (Bim, Bad, Bid, Bik, Noxa,
Puma, Moap-1 and Hrk) as well as multidomain pro-apoptotic (Bak, Bax and Bok) and pro-survival
members (Bcl-2, Bcl-w, Mcl-1, Bcl-XL, and A1/Bfl-1). Through physical interactions, the interplay
between the pro-apoptotic and pro-survival Bcl-2 members regulates apoptosis signaling at the
mitochondria. The physiological roles of distinct Bcl-2 family members are largely unmasked by
genetically engineered murine models. Mcl-1 is one of the two proteins among the Bcl-2 family of
protein whose germline deletion causes embryonic lethality in mice. Extensive studies on tissue- and
cell type-specific gene deletion murine model systems have established the non-redundant in vivo role
of Mcl-1 in a broad range of cell types. This includes hematopoietic stem cells and multiple cell
lineages along their differentiation hierarchy, epithelial cells in the thymus, mammary gland and liver,
cardiomyocytes, endothelial cells, neurons and oocytes. Moreover, emerging evidence suggests that
human and mouse Mcl-1 protein shows differences in certain aspects. Indeed, inhibitors with high
affinity and specificity to human Mcl-1 have been successfully generated. To facilitate the pre-clinical
studies of Mcl-1 in cancer and other diseases, transgenic mouse models over-expressing human Mcl-1
as well as humanized Mcl-1 mouse models have been engineered. This review discusses the current
advances in understanding the physiological roles of Mcl-1 based on studies using murine models and
its implications in treatment of human diseases.