MACROD1 (MACRO domain containing 1)

2010-05-01 Weidong Han , Xiaoyin Ma , Yukun Duan , Zhiqiang Wu Affiliation

Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing 100853, China

Identity

HGNC

MACROD1

LOCATION

11q13.1

IMAGE

LOCUSID

28992

ALIAS

LRP16

FUSION GENES

Show Gene Fusions

DNA/RNA

Note

MACROD1/LRP16, encoding a 35 kD protein, was originally isolated from human lymphocytes. The proximal region (nt-676 to -24) of the human LRP16 promoter contains a 1/2 estrogen response element (ERE)/Sp1 site and multiple GC-rich elements that confer estrogenic responsiveness and are sufficient for estrogenic action. In the presence of estrogen, ERalpha and Sp1 complex recruits to the LRP16 gene promoter to enhance LRP16 transcription.

Description

Genomic structure of LRP16: spans 167 kb; 11 exons; ORF: 975 bp.

Transcription

LRP16 mRNA (NM_014067.3) has a size of 1256 bp.
Exons: 11; transcript length: 1256 bp; translation length: 325 residues.

Pseudogene

No pseudogenes reported.

Proteins

Note

MACROD1/LRP16 contains a single macro domain (Appr-1"-pase_ like). It contains an ADP-ribose-binding pocket through which it can bind mono (ADP-ribose). Moreover, LRP16 also can bind poly (ADP-ribose) and hydrolyze ADP-ribose-1" phosphate to yield ADP-ribose. Therefore, it is reasonable to propose that LRP16 may play an important role in the ADP-ribosylation of proteins, an important post-translational modification which occurs in DNA repair, transcription, chromatin biology, and long-term memory formation.

Description

325 amino acids; 35.505 kDa; containing a single macro domain (from amino acid 141 to 322).

Expression

LRP16 is expressed ubiquitously in nearly all types of tissues and is up-regulated in hormone-dependent cancer cells such as MCF-7 breast cancer cells, Ishikawa endometrial cancer cells, and BG-1 ovarian cancer cells upon estrogenic stimulation. Conversely, estrogen reduces LRP16 expression in estrogen-resistant SKOV-3 ovarian cancer cells. Androgen also up-regulates LRP16 expression in androgen-sensitive prostate cancer cells. In addition, LRP16 is frequently over-expressed in several tumor tissues by comparison with their corresponding normal tissues.

Localisation

Nuclear, cytoplasm and mitochondrion.

Function

1. LRP16 can recruit to DNA-damaged sites through sensing radiation-induced activation of poly-ADP-ribose polymerase-1 (PARP1).
2. LRP16 can interact with both ERalpha and AR to enhance their transcriptional activities.
3. Cytokeratin 18 (K18) can interact with LRP16 through its C-terminal region and sequester LRP16 in the cytoplasm, by which the LRP16 co-activation of ERalpha is inactivated.
4. LRP16 can bind to p65, a component of NF-kappaB, and participates into the NF-kappaB enhanceosome to enhance TNFalpha-induced NF-kappaB activity (our unpublished data).

Homology

- Bos taurus: MACROD1;
- Pan troglodytes: MACROD1;
- Canis lupus familiaris: MACROD1;
- Rattus norvegicus: Macrod1;
- Mus musculus: Macrod1;
- Danio rerio: zgc: 92353;
- Magnaporthe grisea: MGG_09394;
- Neurospora crassa: NCU07925.1.

Implicated in

Entity name

Prostate cancer

Note

Androgen up-regulates LRP16 expression in both mRNA and protein levels in androgen-sensitive prostate cancer cells such as LNCaP cells, but not in prostate cancer cells without overexpression of LRP16, which significantly stimulates cell growth in the presence of androgen. Reversely, inhibition of the endogenous LRP16 in androgen-sensitive prostate cancer cells markedly diminishes androgen-stimulated cell growth. LRP16 is not only a target of AR in androgen-sensitive prostate cancer cells, but also a coactivator of AR. By the AR-LRP16 feedback pathway, LRP16 may play an important role in the progression of androgen-sensitive prostate cancers.

Entity name

Estrogen-dependent breast cancer and endometrial cancer

Note

LRP16 is not only a target gene of ERalpha, but also an ERalpha coactivator. LRP16 overexpression significantly promotes MCF-7 cell proliferation. Reversely, knockdown of LRP16 in MCF-7 cells markedly impaired estrogen-stimulated ERalpha activity and cell growth. LRP16 overexpression was observed in more than 30% primary breast cancers.
LRP16 represses E-cadherin (a molecule associated with cell adhesion and tumor metastasis) expression through antagonizing the binding of ERalpha to the E-cadherin promoter. Inhibition of LRP16 expression in both estrogen-responsive MCF-7 breast cancer and Ishikawa endometrial cancer cells significantly attenuates their invasive capacity.
Collectively, LRP16 may be involved in the progression of estrogen-dependent cancers.

Entity name

Gastric carcinoma

Note

The expression level of LRP16 in primary gastric carcinoma tissues was significantly higher than that in normal mucosa tissues. In addition, overexpression of LRP16 was positively linked with tumor size, depth of invasion, lymph node metastasis, distant metastasis and TNM stage. Higher expression of LRP16 predicts a poor prognosis of gastric carcinoma patients.

Entity name

Colorectal carcinoma

Note

The higher expression level of LRP16 was found to be positively associated with the poor differentiation of primary human colorectal carcinomas. In addition, higher expression of LRP16 in primary human colorectal carcinomas was also linked to poor prognosis of patients.

Prognosis

LRP16 overexpression predicts a poor prognosis in several tumors.

Entity name

t(11;21)(q13;q22) in myelodysplastic syndrome

Hybrid gene

A kind of chromosome rearrangement t(11;21)(q13;q22), involved in RUNX1 (also known as AML1) and LRP16, was found in a patient with monocytic leukemia evolving from myelodysplastic syndrome (MDS). The fusion junction of hybrid gene RUNX1-LRP16 has two types, involving either exon 5 or exon 6 of RUNX1 and exon 2 of LRP16. The reciprocal LRP16-RUNX1 chimera is a fusion between exon 1 of LRP16 and exon 7 of RUNX1.

Fusion protein

Both RUNX1 (exon 5)-LRP16 and RUNX1 (exon 6)-LRP16 retain the RUNT domain (RD) of RUNX1 and the macro domain of LRP16, whereas reciprocal LRP16-RUNX1 retains the transactivation domain (TA) of RUNX1. The formation of fusion protein RUNX1-LRP16 may lead to the inhibition of myeloid differentiation and contributes to leukemia genesis.

Bibliography

Pubmed ID	Last Year	Title	Authors
19666485	2009	Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler.	Gottschalk AJ et al
12790785	2003	Up-regulation of LRP16 mRNA by 17beta-estradiol through activation of estrogen receptor alpha (ERalpha), but not ERbeta, and promotion of human breast cancer MCF-7 cell proliferation: a preliminary report.	Han WD et al
18206366	2008	GC-rich promoter elements maximally confers estrogen-induced transactivation of LRP16 gene through ERalpha/Sp1 interaction in MCF-7 cells.	Han WD et al
17914104	2007	Estrogenically regulated LRP16 interacts with estrogen receptor alpha and enhances the receptor's transcriptional activity.	Han WD et al
17532767	2007	LRP16 is fused to RUNX1 in monocytic leukemia cell line with t(11;21)(q13;q22).	Imagama S et al
19824120	2009	Clinicopathological significance of LRP16 protein in 336 gastric carcinoma patients.	Li YZ et al
16831279	2006	[Expression and clinical significance of LRP16 gene in human breast cancer].	Liao DX et al
20035625	2009	Keratin 18 attenuates estrogen receptor alpha-mediated signaling by sequestering LRP16 in cytoplasm.	Meng Y et al
17893710	2007	Induction of the LRP16 gene by estrogen promotes the invasive growth of Ishikawa human endometrial cancer cells through the downregulation of E-cadherin.	Meng YG et al
18983849	2009	Differential activities of cellular and viral macro domain proteins in binding of ADP-ribose metabolites.	Neuvonen M et al
19403568	2009	Differential induction of LRP16 by liganded and unliganded estrogen receptor alpha in SKOV3 ovarian carcinoma cells.	Tian L et al
19680243	2009	A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation.	Timinszky G et al
20355243	2010	Clinicopathological significance and prognostic value of LRP16 expression in colorectal carcinoma.	Xi HQ et al
19022849	2009	The single-macro domain protein LRP16 is an essential cofactor of androgen receptor.	Yang J et al
15691879	2005	Mechanism of transcriptional regulation of LRP16 gene expression by 17-beta estradiol in MCF-7 human breast cancer cells.	Zhao YL et al

Other Information

Locus ID:

NCBI: 28992
MIM: 610400
HGNC: 29598
Ensembl: ENSG00000133315

Variants:

dbSNP: 28992
ClinVar: 28992
TCGA: ENSG00000133315
COSMIC: MACROD1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000133315	ENST00000255681	Q9BQ69

Expression (GTEx)

100

150

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
21483817	2011	LRP16 integrates into NF-κB transcriptional complex and is required for its functional activation.	21
19022849	2009	The single-macro domain protein LRP16 is an essential cofactor of androgen receptor.	20
17914104	2007	Estrogenically regulated LRP16 interacts with estrogen receptor alpha and enhances the receptor's transcriptional activity.	19
15691879	2005	Mechanism of transcriptional regulation of LRP16 gene expression by 17-beta estradiol in MCF-7 human breast cancer cells.	14
19824120	2009	Clinicopathological significance of LRP16 protein in 336 gastric carcinoma patients.	12
20355243	2010	Clinicopathological significance and prognostic value of LRP16 expression in colorectal carcinoma.	10
26261536	2015	Aberrant LRP16 protein expression in primary neuroendocrine lung tumors.	8
16831279	2006	[Expression and clinical significance of LRP16 gene in human breast cancer].	7
20035625	2009	Keratin 18 attenuates estrogen receptor alpha-mediated signaling by sequestering LRP16 in cytoplasm.	7
25735744	2015	An LRP16-containing preassembly complex contributes to NF-κB activation induced by DNA double-strand breaks.	7

Citation

Weidong Han ; Xiaoyin Ma ; Yukun Duan ; Zhiqiang Wu

MACROD1 (MACRO domain containing 1)

Atlas Genet Cytogenet Oncol Haematol. 2010-05-01

Online version: http://atlasgeneticsoncology.org/gene/50947/macrod1