Mcl-1 is an antiapoptotic Bcl-2 protein member orginally discovered using subtraction hybridization method from myeloid leukemia cells treated with the survival agent, phorbol ester (Kozopas et al., 1993 ). NCBI Summary:
This gene encodes an anti-apoptotic protein, which is a member of the Bcl-2 family. Alternative splicing results in multiple transcript variants. The longest gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene products (isoform 2 and isoform 3) promote apoptosis and are death-inducing. [provided by RefSeq, Oct 2010]
General function
Cell death/survival, Anti-apoptotic, Apoptosis
Comment
Cellular localization
Cytoplasmic, Nuclear, Mitochondrial
Comment
Mcl-1 protein has a prominent mitochondrial localization, and in that it associates with membranes through its carboxyl hydrophobic tail.
Mcl-1 is also abundant in the light membrane fraction of immature ML-1 cells (Yang et al., 1995). Mcl-1 is sometimes assoiated with the endoplasmic reticulum.
Chen MC, et al 2001 reported te cloning and characterization of a novel nuclear Bcl-2 family
protein, zfMcl-1a, in zebrafish embryo.
Zebrafish
Mc1-1a shows the highest homology to rat Mc1-1 and contains several conserved
BH domains of the Bcl-2 family proteins. It also contains a nuclear
localization signal (NLS). Using EGFP reporter analysis, we verified the
nuclear localization of zfMcl-1a. Deletion of the NLS resulted in distribution
of the fusion protein in the cytoplasm. Northern blot analysis indicated that
zfMcl-1a mRNA is 1.5 kb and was expressed in oocytes and throughout embryonic
development. Notably, the expression of zfMcl-1a transcript was significantly
downregulated during gastrulation. These results suggest that zfMcl-1a is a
novel nuclear Bcl-2 family protein and is likely to play an important role in
zebrafish oogenesis and embryogenesis.
Human Chorionic Gonadotropin Up-Regulates Expression of Myeloid Cell Leukemia-1 Protein in Human Granulosa-Lutein Cells: Implication of Corpus Luteum Rescue and Ovarian Hyperstimulation Syndrome. Chen SU et al. Context: The corpus luteum is a dynamic endocrine structure with periodic development and regression during menstrual cycles. Its lifespan can be prolonged by human chorionic gonadotropin (hCG). However, the signal mechanisms of this phenomenon remain unclear. Objective: Our objective was to investigate the molecular mechanisms of hCG in the maintenance of the viability of granulosa-lutein cells. Design: Granulosa-lutein cells were obtained from women undergoing in vitro fertilization. We examined the effects of hCG on the survival of cultured granulosa-lutein cells. The signal pathway inducing antiapoptotic protein was investigated. Results: hCG enhanced viability of granulosa-lutein cells through antiapoptosis but not proliferation, because the apoptotic marker of annexin V was decreased, but the proliferative markers of Ki67 and proliferating cell nuclear antigen were not increased. Myeloid cell leukemia-1 (Mcl-1) protein, but not B-cell lymphoma protein-2 or B-cell lymphoma protein-xL, was significantly induced by hCG and LH. The granulosa-lutein cells secreted vascular endothelial growth factor that induced endothelial permeability. Mcl-1 small interfering RNA increased DNA fragmentation and diminished the antiapoptotic effect of hCG. hCG induced Mcl-1 expression through the LH/hCG receptor, adenylate cyclase, protein kinase A, and cAMP response element-binding protein signal pathway. Flavopiridol inhibited Mcl-1 production, released cytochrome c, and induced apoptosis of granulosa-lutein cells. Conclusions: We first demonstrate that hCG prevents apoptosis of granulosa-lutein cells through the induction of Mcl-1 protein via the LH/hCG receptor and a cAMP response element-binding protein-dependent pathway. We may have found the molecular mechanism for luteal rescue during early pregnancy. Mcl-1 prevents apoptosis and increases cell viability but not proliferation as mechanisms for luteal rescue. Mcl-1 is a key molecule of hCG signaling.
Expression regulated by
FSH, LH
Comment
The Mcl-1 message in granulosa cells is increased following both PMSG and hCG treatment (Leo et al., 1999).
Ovarian localization
Oocyte, Cumulus, Granulosa, Theca
Comment
Sano M, et al reported
that prominent Mcl-1/EAT immunoreactivity was also
observed in large primary oocytes in 21-week fetal ovary, but was not detected
in primordial germ cells in 23-week fetal testis.
Hartley PS, et al reported developmental Changes in Expression of Myeloid Cell Leukemia-1 in Human Germ Cells during Oogenesis and Early Folliculogenesis.
.
mRNA expression of Mcl-1 and its short form Mcl-1s, Bcl-2, Bax, and BAD was demonstrated in fetal ovary by RT-PCR. Hybridization array analysis suggested a selective increase in Mcl-1 expression between 14 and 18 wk gestation, which was confirmed by quantitative PCR. There was a corresponding change in the expression of Mcl-1 protein, detected by immunohistochemistry, from germ cells at the periphery of the ovary at 14-16 wk to the largest germ cells, including oocytes within newly formed primordial follicles, at 21 wk. Mcl-1 was also expressed by oocytes of primordial and preantral follicles in the adult. Bax and BAD immunostaining was detected in both somatic and germ cells in the fetal ovary, whereas Bcl-2 was restricted to somatic cells: no changes in expression were observed. Apoptotic cells, detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, were observed in all fetal ovaries but were infrequent. These results confirm that Bcl-2 family members are differentially expressed in several cell types within the developing human ovary. Increased mRNA expression and the changing distribution of Mcl-1 in germ cells as they develop into primordial follicles as well as persistence in the growing oocyte in the adult may indicate an important role for this survival/antiapoptotic factor throughout germ cell development and maturation.
Role of the Anti-Apoptotic Proteins BCL2 and MCL1 in the Neonatal Mouse Ovary. Jones RL et al. The mammalian ovarian lifespan is determined at the time of birth through a delicate balance of oocyte survival and apoptosis as primordial follicles form, and the mechanism by which germ cells die is not understood. We hypothesized that two BCL2 family proteins, BCL2 and MCL1, may be responsible for regulating neonatal oocyte survival. Previous work has shown that BCL2 is important for germ cell survival in adult mouse ovaries, but no work has been done to examine its role at the time of birth. To elucidate the effects of BCL2 in the neonatal ovary, we examined ovaries of both Bcl2 overexpressing and knockout transgenic mice. When compared to wild-type mice, neither Bcl2 overexpression nor abrogation significantly altered ovarian histology. Another BCL2 family protein, MCL1, is expressed in human oocytes during ovarian development, suggesting a role for MCL1 in oocyte survival. To test this, we first examined the expression of MCL1 in the newborn mouse ovary. MCL1 was localized to both oocytes and somatic cells dur0ng primordial follicle formation. Subsequently, we used an in vitro organ culture system to identify a role for MCL1 in oocyte survival. We found that inhibition of MCL1 with an antibody to MCL1 in culture resulted in a reduced number of germ cells and an increase in cyst breakdown. Our data demonstrate that while BCL2 is not likely involved in perinatal oocyte survival, MCL1 may be an important regulator of the ovarian primordial follicle reserve.
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: type: null mutation fertility: subfertile Comment: Mcl-1 is a key regulator of the ovarian reserve. Omari S et al. (2015) A majority of ovarian follicles are lost to natural death, but the disruption of factors involved in maintenance of the oocyte pool results in a further untimely follicular depletion known as premature ovarian failure. The anti-apoptotic B-cell lymphoma 2 (Bcl-2) family member myeloid cell leukemia-1 (MCL-1) has a pro-survival role in various cell types; however, its contribution to oocyte survival is unconfirmed. We present a phenotypic characterization of oocytes deficient in Mcl-1, and establish its role in maintenance of the primordial follicle (PMF) pool, growing oocyte survival and oocyte quality. Mcl-1 depletion resulted in the premature exhaustion of the ovarian reserve, characterized by early PMF loss because of activation of apoptosis. The increasingly diminished surviving cohort of growing oocytes displayed elevated markers of autophagy and mitochondrial dysfunction. Mcl-1-deficient ovulated oocytes demonstrated an increased susceptibility to cellular fragmentation with activation of the apoptotic cascade. Concomitant deletion of the pro-apoptotic Bcl-2 member Bcl-2-associated X protein (Bax) rescued the PMF phenotype and ovulated oocyte death, but did not prevent the mitochondrial dysfunction associated with Mcl-1 deficiency and could not rescue long-term breeding performance. We thus recognize MCL-1 as the essential survival factor required for conservation of the postnatal PMF pool, growing follicle survival and effective oocyte mitochondrial function.//////////////////
Species: mouse
Mutation name: Mcl-1 knockout
type: null mutation fertility: embryonic lethal Comment: Deletion of Mcl-1 resulted in peri-implantation embryonic lethality Rinkenberger et al. 2000 .