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FLASH GENE

Symbol

MAD1L1

contributors: npt/mct/pgu - updated : 25-01-2016

HGNC name	MAD1 mitotic arrest deficient-like 1 (yeast)
HGNC id	6762

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	7p22.3      Physical location : 1.855.427 - 2.272.583
Synonym name	TAX binding protein 181
	mitotic arrest deficiency protein 1
	MAD1-like 1
Synonym symbol(s)	TXBP181, PIG9, MAD1, TP53I9

DNA

TYPE	functioning gene
STRUCTURE	417.16 kb     19 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
text structure	no TATA box

MAPPING

cloned

Y

linked

N

status

provisional

Map	pter - PDGFRA - NUDT1 - FTSJ2 - MAD1L1 - PMS2 - cen

RNA

TRANSCRIPTS	type	messenger

text	all variants encode the same protein

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001013837 19 - 2714 NP_001013859 - 718 - 1999 10049595 NM_001013836 19 - 2717 NP_001013858 - 718 - 1999 10049595 NM_003550 19 - 2754 NP_003541 - 718 - 1999 10049595

EXPRESSION

Type	ubiquitous

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 Lymphoid/Immune spleen       highly   thymus       highly Respiratory respiratory tract larynx     highly Skin/Tegument skin       highly

cell lineage

cell lines

fluid/secretion

at STAGE

cell cycle

cell cycle, checkpoint, M exit

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	two highly conserved domains, Sin3-interacting domain (SID)
	and basic helix-loop-helix leucine zipper domain (bHLHzip), which are essential for the function during molecular switching from proliferation to differentiation
	C-terminal domain is a part of an extensive kinetochore-binding interface of MAD1L1, and rationalize graded kinetochore targeting of MAD1L1 during checkpoint signaling

mono polymer

homomer , dimer

HOMOLOGY

interspecies

homolog to yeast (mitotic arrest deficient) MADH1

Homologene

FAMILY	ezrin-radixin-moesin family
	MAD1 family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,cytosolic
	intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
	intracellular,cytoplasm,cytoskeleton,microtubule,mitotic spindle
	intracellular,nucleus,chromatin/chromosome,centromere
	intracellular,nucleus,chromatin/chromosome,kinetochore
text	associated with microtubule-unattached kinetochores in mitotic cells and is a component of the spindle assembly checkpoint (SAC)
	localise to kinetochores with BUB1B and MAD2L1
	kinetochore localization of MAD1L1 is sufficient for a metaphase arrest that depends on MAD1L1-MAD2L1 binding

basic FUNCTION	preventing the onset of anaphase until all chromosomes are properly aligned at the metaphase plate
	playing a role in mitotic checkpoint
	acting in a surveillance mechanism that mediates a metaphase delay in response to nonexchange chromosomes
	involved in cell growth control and inhibition of entry into S phase until late G1
	playing a complex role in the development of small-cell lung cancer as well as other tumors
	required for MAD2L1 localization to kinetochores and the association of MAD2L1 with the kinetochore is a pre-requisite for its SAC functionb
	Myc antagonist, upstream regulator of MAD2L1, that forms a tight core complex with MAD2L1 and facilitates MAD2L1 binding to Cdc20
	plays an important role in proper mitotic progression
	IK is a spindle pole-associated protein that colocalizes with MAD1L1 at the spindle poles in metaphase and anaphase
	its overexpression causes aneuploidy and chromosomal instability through weakening mitotic checkpoint signaling caused by mislocalization of the MAD1L1 binding partner MAD2L1
	MAD2L1 is one of the key components of the spindle and mitotic checkpoint complex that regulates the fidelity of cell division along with MAD1L1, CDC20, BUB1B

CELLULAR PROCESS	cell cycle, checkpoint
	cell life, differentiation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	essential component of the mitotic spindle assembly checkpoint
	component of the SAC and form an heterodimer with MAD2L1 at the nuclear pore complex as a cell enters mitosis

INTERACTION

DNA

RNA

small molecule

protein	interacting as an homodimer with MAD2L1
	associating and inactivating the anaphase promoting complex (APC)
	interaction of NUP153 with the spindle assembly checkpoint protein MAD1L1 is important in the regulation of the spindle checkpoint
	interacting with MAD2L1 (recruitment of the spindle-assembly checkpoint protein MAD2L1, through MAD1L1, to non-bioriented kinetochores is needed to stop cell-cycle progression)
	binds to the CDH1 promoter region (regulates the expression of CDH1 and prevents cell migration)
	CNOT3 negatively regulates the expression of MAD1L1, which is evidenced by the stabilization of MAD1L1 mRNA upon CNOT3 depletion
	IK interacts with the human SAC protein MAD1L1
	unexpected connection of NUP107 with the mitotic spindle assembly checkpoint protein MAD1L1
	TPR is required for normal SAC response by stabilizing MAD1L1 and MAD2L2 before mitosis
	MAD1L1 plays a minor role in influencing the MAD2L1-dependent regulation of AURKB suggesting that the effects of MAD2L1 on AURKB are independent of the spindle checkpoint complex
	LMO7 interacted with the spindle assembly checkpoint (SAC) protein MAD1L1

cell & other

REGULATION

activated by

TP53 gain of function mutant

Other

hyperphosphorylated when PLK1 is overexpressed and that the kinase activity of PLK1 is required for MAD1L1 to locate to microtubule-unattached kinetochores

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral somatic mutation       in lung cancer and colon cancer tumoral     --low   in lung cancer and colon cancer tumoral   LOH     in breast cancer tumoral somatic mutation       in acute leukaemia constitutional     --over   its up-regulation may promote tumors and cause resistance to current therapies

Susceptibility

to lung cancer

Variant & Polymorphism other	genetic variants in MAD1L1 confer susceptibility to lung cancer, which might result from reduced spindle checkpoint function due to attenuated function of MAD1L1

Candidate gene
Marker	reduced MAD1L1 expression is a new potential diagnostic symptom of tumor metastasis
Therapy target

ANIMAL & CELL MODELS