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FLASH GENE

Symbol

MCL1

contributors: mct/shn - updated : 08-12-2017

HGNC name	myeloid cell leukemia sequence 1 (BCL2-related)
HGNC id	6943

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	1q21.3      Physical location : 150.547.036 - 150.552.136
Synonym name	multiple cutaneous leiomyomata and uterine fibroids
	induced myeloid leukemia cell differentiation protein Mcl-1
	myeloid cell leukemia sequence 1, isoform 1
	Bcl-2-related protein EAT/mcl1
	myeloid cell leukemia ES
	bcl-2-like protein 3
Synonym symbol(s)	MCUL1, TM, EAT, MCL1L, MCL1S, MGC1839, BCL2L3, mcl1/EAT, Bcl2-L-3, BCL2L3, MGC104264, MCL-1

DNA

TYPE	functioning gene
STRUCTURE	5.18 kb     3 Exon(s)

Genomic sequence alignment details
10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   transcription factor
text structure	pomoter contains an array of putative and confirmed transcription
	factor binding sites, including consensus STAT response
	elements, cAMP response elements (CRE), and nuclear factor kappa
	B binding sites

MAPPING

cloned

Y

linked

Y

status

confirmed

Map	cen - D1S2612 - D1S466 - MCL1 - D1S498 - D1S2347 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_021960 3 splicing 4107 NP_068779 - 350 - - 20540941 enhancing cell survival by inhibiting apoptosis isoform 1 or L NM_182763 2 splicing 3859 NP_877495 - 271 - - 20540941 lacks an alternate exon that causes a frameshift isoform 2, or S, or delta TM promotes apoptosis and is death-inducing lacks BH domains 1, 2 and the transmembrane domain NM_001197320 4 splicing 3648 NP_001184249 - 197 mitochondria - 20540941 isoform ES or extra short lacks a portion of exon 1, removing 53 AAs from the PEST region, but retains all three BH domains and the C-terminal transmembrane domain interacting with MCL1-L and inducing mitochondrial cell death MCL-1 short (MCL-1S) 2 splicing 813 MCL-1 short - 271 placenta - 10837489 splicing out of exon 2 during mRNA processing resulting to an altered C terminus leading leading to the loss of BH1, BH2, and the transmembrane domains

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver         Nervous brain         Reproductive male system prostate       Respiratory lung         Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Muscular striatum skeletal

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	large N-terminal domain containing many motifs that
	affect its rate of turnover, localisation and phosphorylation status
	one Bcl-2 homology 1 (BH1) domain
	one Bcl-2 homology 2 (BH2) domain
	one Bcl-2 homology 3 (BH3) domain
	a PEST region rich in putative phosphorylation sites

conjugated

ubiquitinated

HOMOLOGY

interspecies	ortholog to Mcl1, Mus musculus
	ortholog to Mcl1, Rattus norvegicus
	ortholog to MCL1, Pan troglodytes

intraspecies

homolog to BCL2

Homologene

FAMILY

an anti-apoptotic member of the B-cell lymphoma 2 (BCL2) family of proteins

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,cytosolic
	intracellular,nuclear envelope
text	localised to various cellular membranes, including
	the mitochondria and nuclear envelope
	but it also has prominent cytosolic localisation

basic FUNCTION	involved in programmed myeloid cell differentiation
	involved in programing of differentiation and concomitant maintenance of viability but not of proliferation : isoform 1 inhibits apoptosis while isoform 2 promotes it
	essential both early in lymphoid development and later on in the maintenance of mature lymphocytes (B and T)
	essential for preimplantation development and implantation (
	having an antiapoptotic role in various myeloid neoplasms
	may control the fate of cells
	essential modulator of survival during the development and maintenance of a variety of cell lineages
	blocks the progression of apoptosis by binding and
	sequestering the pro-apoptotic proteins BCL2 homologous
	antagonist killer (BAK) and BCL2-associated protein X (BAX) which are capable of forming pores in the mitochondrial membrane
	MCL1 but not BCL2L1 to be indispensable for the formation and persistence of germinal centers (GCs), and B cell memory
	main anti-apoptotic regulator of activated B cell survival
	MCL1 and BCL2L1 function in the same apoptotic pathway
	coordinately regulates apoptosis and autophagy, the outcome being determined by the interplay between BAX and Beclin-1 activation downstream of MCL1 degradation
	coordinately regulates apoptosis and autophagy in a context-dependent manner
	combination of BCL2L1 and MCL1 is essential for the viability of the megakaryocyte lineage

CELLULAR PROCESS	cell cycle, progression
	cell life, antiapoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	Bcl-2-related ovarian killer, Bok (
	defender against cell death 1, DAD1 (
	proliferating cell nuclear antigen, PCNA (
	Bcl-xl/Bcl-2-associated death promoter homolog, BAD
	Fortilin (
	Tankyrase 1, TANK1 (
	BCL2-antagonist/killer, BAK (
	Immediate early gene X-1, IEX-1 (
	Mcl-1 ubiquitin ligase E3, Mule (
	LASU1 (
	coordinated action of MCL1, IER3, and BCL2L11 controls cell death and survival (new regulatory circuit)
	Beclin-1 in the mitochondria
	BAX BH3 domain complexing with the pro-survival proteins MCL1 and BCL2L1
	PMAIP1 is strongly upregulated and became associated with both MCL1 and BCL2L11 during apoptosis induced by proteasome inhibition
	SCF(FBW7) (
	ubiquitin specific peptidase 9, X-linked, USP9X
	PMAIP1 is involved in the modulation of MCL1 expression
	PMAIP1 favors the interaction between MCL1 and HUWE1 and consequently affects MCL1 ubiquitination
	ATG12 directly regulates the apoptotic pathway by binding and inactivating prosurvival BCL2 family members, including BCL2 and MCL1
	NAA10 positively regulated MCL1 expression, as exogenous NAA10 promoted MCL1 expression, whereas NAA10 silencing decreased MCL1 expression
	NAA10 inhibits apoptosis through NAA10-RELA-dependent MCL1 transcriptional activation
	antagonism between MCL1 and BBC3 governs stem/progenitor cell survival during hematopoietic recovery from stress
	EXOC4 is involved in the regulation of both BCL2 and MCL1 at the mRNA level
	EXOC3 regulated BCL2 at the mRNA level and the binding affinity of F-box and WD repeat domain containing 7 and MCL1, thereby controlling MCL1 at the protein level
	ASAH1 plays a critical role in AML survival through regulation of both sphingolipid levels and MCL1
	mitochondrial fission proteins DNM1L and MFF negatively regulate MARCH5 activity toward MIEF2 and MCL1
	macrophages confer survival signals via CCR1-dependent translational MCL1 induction in chronic lymphocytic leukemia
	BCL2 proteins directly promote SUFU turnover, inhibit SUFU-GLI interaction, and induce the expression of the GLI target genes BCL2, MCL1 and BCL2L1
	MCL1 is an upstream stress-sensitive protein, functional in AMBRA1-mediated mitophagy
	MCL1 stability is regulated by the kinase GSK3B and the E3 ubiquitin ligase HUWE1 in regulating AMBRA1-mediated mitophagy

cell & other

REGULATION

Other

MCL1 degradation can occur independently of ubiquitinylation

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in NPM-ALK positive anaplastic large cells lymphoma tumoral     --over   in rhabdomyosarcoma tumoral     --over   in severalhaematological cancers and solid tumours, including chronic myeloid leukemia and hepatocellular carcinoma

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer hemopathy   attractive target and survival factor in neoplastic mast cells in systemic mastocytosis cancer     attractive and potential therapeutic target in a number of malignancies cancer hemopathy   potential target in germinal center-derived lymphomas that do not overexpress BCL2L1

ANIMAL & CELL MODELS

	Deletion of Mcl-1 resulted in peri-implantation embryonic lethality in mouse (
	mice conditional for Mcl-1 display a profound reduction in B and T lymphocytes when MCL-1 is removed, deletion of Mcl-1 during early lymphocyte differentiation increased apoptosis and arrested the development at pro-B-cell and double-negative T-cell stages (
	deletion of Mcl-1 in cortical neurons of transgenic mice activates a robust autophagic response