MCL1 provides a window on the role of the BCL2 family in cell proliferation, differentiation and tumorigenesis

Abstract

The MCL1 gene (myeloid cell leukemia-1) was discovered serendipitously about a decade ago and proved to be a member of the emerging BCL2 gene family. Ongoing studies of this gene provide an interesting perspective on the role of the BCL2 family in transitions in cell phenotype. Specifically, gene products that influence cell viability as a major effect (eg MCL1, BCL2 and other family members) can act as key determinants in cell proliferation, differentiation and tumorigenesis. Although they do not have a direct role in proliferation/differentiation programs, these genes can either permit these programs to proceed or prevent them. Through such effects, the BCL2 family regulates the normal flow of cells through cycles of proliferation and along various pathways of differentiation. A model is presented suggesting that this is accomplished by sustaining or inhibiting viability at critical points in the cell lifecycle. These critical points represent windows of time during which cell fate transitions are effected. They can also be visualized as windows that open or close to promote or prevent continued progression along various cell fate pathways. The pattern of BCL2 family expression at these points allows for the proliferation differentiation, and continued viability of cell types that are needed, while aborting these processes for cells that are overabundant or no longer needed. The combined action of the various family members can therefore control the fate of cells, tissues and even the organism. This mechanism involving apoptosis-related genes is readily executable, and is poised to respond to external signals through the differential regulation of BCL2 family members. As such, it plays an important role in the maintenance of tissue homeostasis and function. Alterations that affect the BCL2 family impair the capacity to control the flow of cells through these critical points, and thereby 'leave the window open' for cell immortalization and cancer. Targeting this family may thus provide a means of inhibiting cancer development and inducing apoptosis in tumor cells. Leukemia (2002) 16, 444-454. DOI: 10.1038/sj/leu/2402416 Keywords: MCL1; BCL2; apoptosis; differentiation; hematopoiesis; cancer MCL1 was discovered based on increased expression during cell commitment to differentiation MCL1 was originally identified as a gene up-regulated early in the differentiation of a human myeloid leukemia cell line, ML-1. 1 These cells proliferate at an immature myeloblastic stage and undergo terminal differentiation to non-proliferative monocyte/macrophages upon exposure to phorbol esters such as 12-0-tetradecanoylphorbol 13-acetate (TPA). Commitment to differentiation occurs rapidly -within a window of several hours -upon the application of TPA to growth-arrested cells. 2 The 'commitment window' precedes phenotypic differentiation, which proceeds over the next several days. ML-1 cells that have passed through the commitment window do not difCorrespondence: RW Craig, Department of Pharmacology and Toxicology, Dartmouth Medic...

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

“…Expression of the pro-survival gene Mcl1, a member of the BCL2 family and a crucial regulator of HSC survival, has been implicated in the pathogenesis of AML. 33,34 Recent studies have shown that MCL1 contributes to chemoresistance and disease relapse. 35,36 FLT3 ITD has been shown to stimulate MCL1 expression in HSCs and LICs via the STAT5-dependent signaling pathway.…”

The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1

“…From these results, we suggest endogenous IL-6 as a survival factor in our cellular model. Mcl-1, which is highly expressed in hematopoietic cells, is an antiapoptotic member of the Bcl-2 family (Craig, 2002). In multiple myeloma (MM) cells, in which IL-6 plays a critical role in proliferation and survival, upregulation of Mcl-1 was shown to mediate the antiapoptotic effect of IL-6 (Jourdan et al, 2003), whereas the downregulation of the gene by antisense technology led to apoptosis (Derenne et al, 2002;Zhang et al, 2002;Le Gouill et al, 2004).…”

“…We previously demonstrated that LNCaP-IL-6 þ cells lack the proapoptotic Bax and overexpress the antiapoptotic Bcl-2 proteins compared to the control cells (Steiner et al, 2006). We here considered another important regulator of apoptosis, myeloid cell leukemia 1 (Mcl-1) , originally identified as an early gene induced during differentiation of ML-1 myeloid leukemia cells (Kozopas et al, 1993;Craig, 2002). Mcl-1's role in the regulation of cell death has been mostly investigated in myeloma cells in which it mediates the prosurvival action of IL-6 (Jourdan et al, 2003).…”

Unraveling MCL-1 degradation

“…MAP kinases, PI3K/Akt, and JAK/ STAT). 6 Furthermore, like Bcl-X, Mcl-1 has been shown to be post-transcriptionally regulated through alternative splicing to form a proapoptotic molecule (MCL-1 S ) made up of exons 1 and 3. 6 MCL-1 is also regulated by phosphorylation in response to a variety of cell stimuli.…”