BMP4 (bone morphogenetic protein 4)

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BMP4 (bone morphogenetic protein 4)

Identity

Other names	BMP2B
	BMP2B1
	MCOPS6
	OFC11
	ZYME
HGNC (Hugo)	BMP4
LocusID (NCBI)	652
Location	14q22.2
Location_base_pair	Starts at 54416455 and ends at 54423554 bp from pter ( according to hg19-Feb_2009) [Mapping]
Local_order	Genes flanking BMP4 at 14q22.2 are (centromeric to telomeric): MIR5580 (microRNA 5580), BMP4, ATP5C1P1 (ATP synthase, H+ transporting, mitochondrial F1 complex, gamma polypeptide 1 pseudogene 1).

DNA/RNA

Description	Gene spans approximately 9 kbp on the minus strand at 14q22.2.
Transcription	Alternative splicing in the 5'UTR gives rise to 3 transcript variants, all encoding an identical protein. Transcript variant 1 is 1917 bp in length with 4 exons (2 coding exons), transcript variant 2 is 1708 bp in length with 4 exons (2 coding exons), and transcript variant 3 is 1705 bp in length with 3 exons (2 coding exons). In Xenopus embryos, BMP4 itself, along with the homeobox genes Vox, X-vent1, X-vent2, GATA-1, GATA-2 and AP-1 were found to induce the expression of BMP4 and control dorsoventral patterning in the mesoderm (Jones et al., 1992; Kim et al., 1998; Onichtchouk et al., 1996; Schmidt et al., 1996), whereas organizer signals, chordin and noggin, and X-lim1 negatively regulate BMP4 transcription (Kim et al., 1998). Lung specification in Xenopus depends on the suppression of BMP4 expression by zinc-finger transcriptional repressors Osr1 and Osr2 (Rankin et al., 2012). Analysis of the mouse BMP4 gene identified 2 G-C rich Sp1 binding motifs proximal to the transcriptional start sites for exons I and II (Kurihara et al., 1993). The presence of dual promoter regions flanking exons I and II were later confirmed in human cancer cell lines (van den Wijngaard et al., 1996). Mouse BMP4 is negatively regulated by direct binding of chicken ovalbumin upstream-transcription factor I (COUP-TF1) to the proximal promoter of exon I (Feng et al., 1995). Deletion analysis of the mouse BMP4 promoter in MC3T3E1 cells identified a cis-acting E-box element proximal to the transcriptional start site that is bound by upstream regulatory factor (USF), a member of the helix-loop-helix family of regulatory proteins (Ebara et al., 1997). In mouse development, GATA-4 and -GATA-6 were found to specifically regulate BMP4 transcription to mediate endoderm-mesoderm signalling and early vasculogenesis (Nemer et al., 2003). Similarly, analysis of mouse embryonic stem cells identified the transcriptional corepressor Bcor as an important regulator of ES cell differentiation into mesoderm, ectoderm and hematopoietic lineages through regulating developmental genes including BMP4 expression (Wamstad et al., 2008). Furthermore, the transcription factor Cdx2 has been shown to directly regulate BMP4 expression in mouse trophoblast cells to promote early mouse embryogenesis (Murohashi et al., 2010), while Shox2 regulates BMP4 expression to promote pacemaker development in the murine heart (Puskaric et al., 2010). Analysis of the human BMP4 promoter in U2OS and SaOS2 cells identified the lack of a proximal TATA box, while sharing similar transcriptional start sites and regulatory elements with the mouse BMP4 promoter (Helvering et al., 2000; Shore et al., 1998). Putative binding motifs for AP1, Sp1, CRE, Cfab1 were identified, and direct binding of Cfab1 to the BMP4 promoter was confirmed, along with transcriptional upregulation of BMP4 by osteogenic compounds such as retinoic acid and the phorbol ester PMA (Helvering et al., 2000). Transcriptional control of BMP4 is also important in diseased states. During recovery from acute anemia, hypoxia induces BMP4 expression and subsequent erythropoiesis in the murine spleen through direct binding of HIF2alpha to the BMP4 promoter (Wu et al., 2010). In retinal pigment epithelium cells of patients suffering from the wet form, but not the dry form, of macular degeneration, TNFalpha represses BMP4 transcription through phosphorylation of the transcription factor Sp1, demonstrating a BMP4 expression-dependent molecular switch (Xu et al., 2011). In hepatocellular carcinoma cells, Ets-1 was demonstrated to directly regulate hypoxia-induced BMP4 transcription to promote tumorigenesis (Maegdefrau et al., 2009). In colorectal cancer cells, oncogenic KRAS can repress BMP4 expression through a novel ras-responsive region (Duerr et al., 2012). In addition to many proximal regulatory sites, the BMP4 gene, along with many other BMP family genes, resides within a conserved gene desert, which contains many additional distal cis-regulatory regions (located over 30 kbp from coding sequences) that control BMP4 expression in a spatiotemporal and tissue-dependent manner (Chandler et al., 2009; Pregizer et al., 2009). For example, an evolutionarily conserved distal enhancer site, 46 kb upstream of the transcriptional start site, is bound by Pitx2 and likely participates in tooth and limb morphogenesis (Jumlongras et al., 2012). Furthermore, a common polymorphism found within the distal BMP4 promoter (17kb upstream) acts as a cis-acting enhancer of BMP4 transcription, and is significantly associated with colorectal cancer risk (Lubbe et al., 2012).
Pseudogene	None annotated.

Protein

Description	BMP4, a member of the TGFbeta superfamily of signalling molecules, is a 46.5 kDa, 408 aa protein that is translated as a precursor containing a signal peptide (aa 1 - 19), a prodomain (aa 20 - 292) and a mature domain (aa 293 - 408). After the BMP signal peptide has been removed, dimerization of the proproteins proceeds. Proprotein cleavage is achieved by the candidate serine endoproteases Furin, PCSK5, PCSK6, or PCSK7 at the consensus sequence RXXR, resulting in the generation and secretion of biologically active molecules (Bragdon et al., 2011; Cui et al., 1998; Goldman et al., 2006; Shimasaki et al., 2004). As with other TGFbeta family members, BMP4 is a cysteine knot-containing, disulfide-linked dimer (Jones et al., 1994; Shimasaki et al., 2004), containing a conserved TGF-beta propeptide domain (pfam00668) and transforming growth factor beta like domain (cl02510). One high-throughput study has identified a ubiquitination site at Lys-185 (Kim et al., 2011).
Expression	The amino acid sequence for BMP4 was first derived from an isolated preparation of bovine bone (Wozney et al., 1988). Human BMP4 was cloned from a placental cDNA library (Oida et al., 1995). Apart from its high expression in developing embryonic tissues (Chen et al., 2004), BMP4 was determined by microarray analysis to be highly expressed in adult tissues such as the thymus, spleen, brain, heart, muscle, kidney, lung, liver, pancreas, and prostate (Schmueli et al., 2003; Yanai et al., 2005). Immunohistochemical analysis of adult tissues shows high expression in epithelial cells of the skin, bladder and stomach (Alarmo et al., 2012). In tumors, BMP4 is expressed in melanoma, ovarian, gastric, basal cell, renal and squamous carcinomas of the head and neck (Chiu et al., 2012; Deng et al., 2007; Davies et al., 2008; Giacomini et al., 2006; Johnson et al., 2009; Kim et al., 2011; Kwak et al., 2007; Laatio et al., 2011; Lombardo et al., 2011; Sneddon et al., 2006; Rothhammer et al., 2005; Xu et al., 2011). Overexpression of BMP4 in comparison to normal tissues is observed in breast, ovarian, gastric, hepatocellular and colorectal carcinomas (Alarmo et al., 2012; Chiu et al., 2012; Deng et al., 2007; Kim et al., 2011).
Localisation	BMP4 is a secreted protein localized within the extracellular milieu (Chen et al., 2004), but has also been shown to localize within the cytoplasm in vesicles directed for lysosomal degradation, in order to tightly mitigate BMP4 signalling (Kelley et al., 2009).
Function	BMP4 is a member of the bone morphogenetic protein family, which is part of the transforming growth factor-beta superfamily of growth and differentiation factors. Bone morphogenetic proteins were originally identified by an ability of demineralized bone extract to induce endochondral osteogenesis in vivo in an extraskeletal site (Urist, 1965), but are now considered essential factors with varying roles during embryogenesis, skeletal formation, hematopoiesis and neurogenesis (Bragdon et al., 2001; Chen et al., 2004; Kallioniemi, 2012). In adult tissues, BMP4 signalling can control many cellular behaviours including differentiation, proliferation, apoptosis, and motility (Kallioniemi, 2012). The mature BMP4 dimer binds to type I and II serine-threonine kinase receptors, and the constitutively active BMP type II receptor will phosphorylate the type I receptor upon ligand binding (Miyazono et al., 2010; Nohe et al., 2004). The activated type I BMP receptor is then able to phosphorylate the cytosolic receptor-regulated SMAD proteins (Attisano et al., 2000; Bragdon et al., 2001; Miyazono et al., 2010), which will then form a complex with the common SMAD4, translocate to the nucleus to regulate gene transcription (Feng et al., 2005; ten Dijke et al., 2003). In addition to this canonical SMAD-dependent signaling pathway, BMP4 can signal through SMAD-independent means to directly induce ERK and p38 MAPKs, JNK, NFkB, PI3K, PKA, PKC and PKD signaling pathways affecting cell survival, apoptosis, migration and differentiation (Bragdon et al., 2011). In addition to intracellular regulation, BMP4 signals can be modulated at the receptor level through interaction with three different type I (BMPR1A [ALK3], BMPR1B [ALK6], and ACVR1A [ALK2]) and type II (BMPR2, ACVR2A [Act-RII], and ACVR2B [Act-RIIB]) receptors (Kawabata et al., 1998; Miyazono et al., 2010; Nohe et al., 2004), and negatively regulated by interaction with the pseudoreceptor BAMBI (Onichtchouk et al., 1999). BMP4 signalling can also be regulated at the extracellular level through binding to the endogenous inhibitors tsg (Twisted gastrulation) and Follistatin, and those belonging to the Dan family (Dan, Gremlin, Gremlin2, Cerberus, Coco, Caronte, Ectodin, and Sclerostin), and the Chordin family (Chordin, Chordin-like-2, Noggin) of BMP antagonists (Bragdon et al., 2011).
Homology	There are BMP4 homologs in several vertebrate species, including chimpanzee, rhesus monkey, dog, cow, chicken, rat, mouse, lizard, frog (Xenopus laevis), and zebrafish (Danio rerio) and in invertebrates such as the fruit fly (Drosophila melanogaster) and the worm (Caenorhabditis elegans).

Mutations

Germinal

Heterozygous mutations in exons 3 and 4 of the BMP4 gene resulting in decreased expression were found in children with cleft lip and cleft palate (Suzuki et al., 2009), including: a 1037C-T transition resulting in an A346V substitution; a 271A-T transversion resulting in a S91C substitution; a 860G-A transition resulting in an R287H substitution; and a 592C-T transition resulting in an R198X substitution.
Three pathogenic germline mutations were identified in a cohort of 504 genetically enriched colorectal cancer cases. p.R286X (g.8330C>T) localizes to the N-terminal of the prodomain truncating the protein prior to the active domain; p.W325C (g.8449G>T) and p.C373S (g.8592G>C) mutations are predicted from protein homology modelling with BMP2 to impact deleteriously on BMP4 function; and p.C373S (g.8592G>C) segregates with adenoma and hyperplastic polyps in first-degree relatives, suggesting this germline mutation may confer a juvenile polyposis-type phenotype (Lubbe et al., 2011).

Somatic

Four substitution missense mutations have been identified: two mutations were detected in two different single prostate tumors (c.344A>T, p.N115I (Grasso et al., 2012), c.857G>A, p.R286Q (Barbieri et al., 2012), and two in two different large intestinal carcinoma tumors (c.631C>T, p.R211W, and c.1222C>T, p.R408C)) (The Cancer Genome Atlas Network, 2012).

Implicated in

Entity	Fibrodysplasia ossificans progressiva (FOP)
Prognosis	Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and disabling autosomal dominant genetic disorder with complete penetrance characterized by congenital malformations of the great toes and by progressive heterotopic endochondral ossification in predictable anatomical patterns. Ectopic expression of BMP-4 was found in FOP patients (Gannon et al., 1997; Xu et al., 2000).
Cytogenetics	Overexpression of BMP4 mRNA was found in FOP patients (Shafritz et al., 1996), in addition a heterozygous activating mutation found in the ACVR1 gene (Shore et al., 2006).

Entity	Microphthalmia, syndromic 6 (MCOPS6)
Prognosis	A loss of BMP4 expression can lead to the heritable disorder microphthalmia syndromic type 6 (MCOPS6); also known as microphthalmia and pituitary anomalies or microphthalmia with brain and digit developmental anomalies. Microphthalmia is a clinically heterogeneous disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). MCOPS6 is characterized by microphthalmia/anophthalmia associated with facial, genital, skeletal, neurologic and endocrine anomalies. (Bakrania et al., 2008; Bennett et al., 1991; Elliott et al., 1993; Lemyre et al., 1998; Phadke et al., 1994).
Cytogenetics	Deletions in 14q22-q23 are associated with anophthalmia-microphthalmia, brain, pituitary, and ear anomalies including structural defects and hearing loss, hypothyroidism, poly- and/or syndactyly, clinodactyly, high arched palate, cryptorchidism, and developmental delay (Ahmad et al., 2003; Bennett et al., 1991).

Entity	Oral Facial Cleft 11 (OFC11)
Prognosis	Mutations in the BMP4 gene during development can result in congenital 'healed' cleft lip (CHCL), an unusual heritable anomaly consisting of a paramedian 'scar' of the upper lip with an appearance suggesting that a typical cleft lip was corrected in utero. The CHCL is frequently associated with an ipsilateral notch in the vermilion border and a 'collapsed' nostril (Castilla et al., 1995).
Cytogenetics	Missense and nonsense mutations in the BMP4 gene resulting in decreased expression were found in children with cleft lip and cleft palate (Suzuki et al., 2009).

Entity	Basal-cell carcinoma
Oncogenesis	BMP4 treatment of primary cultures of basal carcinoma cells reduces cell growth and induces the expression of keratinocyte differentiation markers, which can be antagonized by the BMP inhibitor gremlin1 (Sneddon et al., 2006).

Entity	Bladder cancer
Oncogenesis	BMP4 inhibits growth in the RT4 cell line, but no effect is seen in TCC-Sup or TSU-Pr1 cells; expression of BMPR2 in TSU-Pr1 cells restores the growth-inhibitory effect of BMP4 treatment in nude mice (Kim et al., 2004). Through the mining of publicly available whole genome microarray datasets, BMP4 was identified within a set of 17 differentially expressed genes to be downregulated in bladder cancers (Zaravinos et al., 2011).

Entity	Brain cancers
Oncogenesis	BMP4 increased growth and reduced apoptosis of the neuroectodermal tumor cell line DAOY (Iantosca et al., 1999). Treatment of glioblastoma stem cells with BMP4 decreased proliferation and induced differentiation in GBM cells (Piccirillo et al., 2006), cerebellar granule neuron progenitors (GNPs) and primary GNP-like medulloblastoma cells (Zhao et al., 2008), and inhibited glioma stem cell proliferation via G1 arrest and CCND1 while enhancing apoptosis through induction of Bax and inhibition of Bcl-2 and Bcl-xL (Zhou et al., 2011). BMP4-dependent growth inhibitory effects were also seen in the brain glioma cell line U251 (Liu et al., 2011). BMP4 is expressed in meningiomas, and stimulates the proliferative capacity of primary meningioma cell cultures via phosphorylation of Smad 1, but not p38 MAPK (Johnson et al., 2009). Human astrocytomas were found to have methylation of the BMP4 promoter (Wu et al., 2010).

Entity	Breast cancer
Prognosis	BMP4 is highly expressed in primary breast cancer tumors and cell lines (Alarmo et al., 2007), and strong immunohistochemical expression of BMP4 correlates significantly with reduced proliferation and increased rates of recurrence (Alarmo et al., 2012). Methylation of the BMP4 promoter, combined within a four-gene methylation signature, was found predictive of outcome in steroid receptor-positive, node-negative, HER-2 negative breast cancer patients treated with anthracycline (Hartmann et al., 2009).
Oncogenesis	Exogenous treatment of BMP4 abrogates lumen formation in mammary epithelial cells and promotes invasive growth (Montesano, 2007). BMP4 treatment did not affect the proliferative capacity of immortalized mammary epithelial cells, however BMP4 potentiates growth factor-induced proliferation (Montesano et al., 2008). BMP4 treatment of MDA-MB-231 and MCF-7 breast carcinoma cells inhibited MMP expression and activity, decreasing their metastatic potential (Shon et al., 2009). In nine breast cancer cell lines, BMP4 treatment induced growth suppression via G1 arrest, while stimulating cell migration and invasion in a SMAD-dependent manner (Ketolainen et al., 2010). BMP4 treatment of MDA-MB-231 and MCF-7 breast cancer cell lines induced migration and invasion phenotypes via the upregulation of MMP-1 and CXCR4 that could be abrogated by either anti-BMP4 siRNA or Noggin treatment (Guo et al., 2012). BMP4 treatment of multiple breast cancer cell lines and analysis using a whole genome oligo microarray revealed a strong transcriptional response for genes involved in cellular differentiation and transcriptional activity (Rodriguez-Martinez et al., 2011).

Entity	Colorectal carcinoma (CRC)
Prognosis	Three germline pathogenic mutations of BMP4, p.R286X (g.8330C>T), p.W325C (g.8449G>T) and p.C373S (g.8592G>C) were suggested to be causal for colorectal cancer (Lubbe et al., 2011). Three common variants (rs4444235, rs17563, and rs1957636) at the BMP4 locus have been associated with elevated risk of colorectal cancer (Houlston et al., 2008; Lubbe et al., 2012; Slattery et al., 2012; Theodoratou et al., 2012; Tomlinson et al., 2011). Immunohistochemical and real-time mRNA expression analysis of BMP4 in primary tumors correlated strongly with advanced stage and liver metastases (Deng et al., 2007).
Oncogenesis	Germline BMP4 mutations were found to be deleterious to the BMP4 protein in colorectal cancers (Lubbe et al., 2011). Furthermore, a common polymorphism found within the distal BMP4 promoter (17 kb upstream) acts as a cis-acting enhancer of BMP4 transcription, leading to enhanced expression, which is significantly associated with colorectal cancer risk (Lubbe et al., 2012). Overexpression of BMP4 in HCT116 human colorectal cancer cell line promotes in vitro migration and invasion (Deng et al., 2007). In colorectal stem cells isolated from primary tumors, BMP4 treatment induced terminal differentiation, apoptosis and chemosensitization in vitro and in tumour xenografts (Lombardo et al., 2011). BMP4 signalling has been shown to protect HCT116 cells from heat-induced apoptosis by modulating MAPK pathways (Deng et al., 2007), and overexpression of BMP4 can enhance the invasiveness of CRC cells independent of Smad4 activity (Deng et al., 2009).

Entity	Gastric cancer (GC)
Prognosis	Expression of BMP4 is inversely related to prevalence of lymph node metastasis in gastric adenocarcinomas (Kim et al., 2011). BMP4 mRNA was significantly overexpressed in gastric cancers relative to mucosal controls and negatively correlated with BMP4 promoter methylation, while high expression of BMP4 predicted poor outcome (Ivanova et al., 2012).
Oncogenesis	Immunocytochemical analysis of primary gastric tumors revealed that BMP4 was significantly overexpressed in comparison to normal mucosa, and correlated with Helicobater pylori infection. However, the expression of BMP4 negatively correlated with the presence of lymph node metastases and tumor invasiveness (Kim et al., 2011). BMP4 is highly expressed in cisplatin-resistant cell lines, and overexpression induced GC cell line tumorigenicity in vitro, while shRNA-mediated knockdown decreased proliferation, colony formation and restored cisplatin sensitivity (Ivanova et al., 2012). In diffuse-type gastric carcinoma cells lines in vitro, BMP4 acted as a tumor suppressor by inducing cell cycle arrest in these cells via p21 induction through the SMAD pathway (Shirai et al., 2011).

Entity	Hepatocellular carcinoma (HCC)
Prognosis	BMP4 is significantly overexpressed in 60% of primary HCC tumors (Chiu et al., 2012). BMP4 immunohistochemical expression significantly correlated with increased tumor nodules, increasing TMN stage, vascular invasion and tumor invasiveness, and was an independent predictor of disease-free and overall survival in HCC patients (Guo et al., 2012).
Oncogenesis	BMP4 promotes the growth and migration of HCC cell lines in vitro, and BMP4 can induce cyclin-dependent kinase 1 (CDK1) and cyclin B1 upregulation to accelerate cell-cycle progression and metastasis in HCC cells through MEK-ERK signaling (Chiu et al., 2012). In HCC cell lines, BMP4 expression was shown to be induced by hypoxia to promote in vitro migration, invasion, anchorage-independence and tube formation to promote tumor progression (Maegdefrau et al., 2009).

Entity	Lung cancer
Prognosis	Combined with 3 other biomarkers, immunohistochemical expression of BMP4 was shown to predict the risk of bone metastasis in stage III resected non-small cell lung carcinoma (Zhou et al., 2012).
Oncogenesis	Treatment of lung cancer cell line A549 with BMP4 induced a senescent phenotype, characterized by reduced growth, increased size, reduced invasion, and expression of senescence-associated beta-galactosidase. BMP4-treated A549 cells also exhibited decreased growth in mouse xenograft models (Buckley et al., 2004). BMP4 via Smad signalling has also been shown to mediate adriamycin-induced premature senescence in multiple lung carcinoma cell lines (Su et al., 2009). A later study found that cooperativity between p38 MAPK and Smad pathways is required for BMP4-induced senescence (Su et al., 2011).

Entity	Melanoma
Prognosis	Bioinformatics analyses identified polymorphisms within the BMP4 gene (SNPs 6007 C/T (rs17563) and 3445 T/G (rs4898820)) affecting mRNA expression and shows a significant association with cutaneous melanoma (Capasso et al., 2009).
Oncogenesis	BMP4 was found to be overexpressed in melanoma cell lines, and primary and metastatic melanomas compared to nevi. Although no effect was seen on proliferation, BMP4 signalling significanctly increased migration and invasion in melanoma cell lines (Rothhammer et al., 2005). BMP4 was later shown to stimulate angiogenesis in malignant melanomas by inducing tube formation as well as the migratory efficiency of microvascular endothelial cells (Rothhammer et al., 2007).

Entity	Multiple myeloma
Oncogenesis	BMP4 inhibited DNA synthesis and induced G1 arrest and/or apoptosis in OH-2, IH-1 and ANBL-6 cell lines (Hjertner et al., 2001), and induced apoptosis in multiple myeloma cell lines via Smad-dependent down-regulation of MYC (Holien et al., 2012). However, BMP4 was shown to be overexpressed in bone marrow cells derived from multiple myeloma patients, and partially protected myeloma cells from apoptosis induced by the anti-myeloma drug bortezomib (a proteosome inhibitor) (Grcevic et al., 2010).

Entity	Ovarian cancer
Prognosis	One study identified via immunohistochemistry that high BMP4 expression in primary serous ovarian cancer tumors was an independent prognostic factor for longer progression-free survival time and overall survival prior to administration of chemotherapy (Laatio et al., 2011).
Oncogenesis	An autocrine BMP signalling pathway was identified in primary human ovarian surface epithelial cells and primary ovarian cancer cells. Treatment of primary ovarian cancer cells with BMP4 had no effect on proliferative capacity, but long-term cultures showed decreased cell density and increased cell spreading and adherence (Shepherd et al., 2003). Treatment of primary ovarian cancer cells with exogenous BMP4 produced morphological alterations and increased cellular adhesion, motility and invasion, which could be inhibited by Noggin, while primary ovarian surface epithelial cells showed no response to these ligands (Thériault et al., 2007). BMP4 treatment also altered the EMT markers Snail, Slug and E-cadherin, along with an increase in activation of Rho-GTPases, suggesting that ovarian cancer agressive cellular behaviours may be mediated through autocrine BMP4 signalling (Thériault et al., 2007). These BMP4-induced changes in cellular morphology and motility were later found to be Smad-dependent (é et al., 2011). Ovarian cancer tumor-associated mesenchymal stem cells were found to have overexpression of BMP4, suggesting BMP4 may have a role in modulation of the tumor microenvironment to promote tumorigenesis (McLean et al., 2011).

Entity	Pancreatic cancer
Cytogenetics	A CGH study of pancreatic primary tumors, cell lines and xenografts determined a significant recurrent low-level gain of chromosome 14q22.2 in these samples (Nowak, et al., 2005).
Oncogenesis	BMP4 demonstrates overexpression at the mRNA level in 25% of 16 established pancreatic cell lines compared to normal tissues. Treatment of 5 cell lines with BMP4 induced growth suppression via G1 arrest, but significantly increased the migratory and invasive phenotypes of pancreatic cell lines (3 out of 5) in vitro via SMAD-dependent signalling (Virtanen et al., 2011). BMP4 treatment of Panc-1 cells induced an EMT response characterized by increased migration mediated by MSX2 induction (Hamada et al., 2007), while another study demonstrated BMP4 treatment of Panc-1 cells also resulted in an EMT response involving MMP2 activity that was Smad1-dependent (Gordon et al., 2009).

Entity	Prostate cancer
Prognosis	Immunohistochemical analysis of primary prostate cancer tumors and bone metastases revealed that BMP4 was overexpressed in the metastatic deposits, but not the primary tumors suggesting a role for BMP4 expression in promoting prostate cancer metastasis (Spanjol et al., 2010).
Oncogenesis	Treatment of LNCaP cells with BMP4 inhibited proliferation through G1 arrest and induction of p21, however no effect on growth was seen in PC-3 cells (Brubaker et al., 2004). Another study confirmed the growth inhibitory effect of BMP4 on LNCaP cells and found the effect could be abrogated by Noggin treatment (Shaw et al., 2010). In LAPC-4 cells, BMP4 treatment showed no effect on cellular proliferation, migration or invasion (Feeley et al., 2005). However a later study found that BMP4 could promote prostate tumor growth in bone through osteogenesis in the xenograft cell line MDA-PCa-118b (Lee et al., 2011).

Entity	Pituitary tumors
Oncogenesis	BMP4 has cell-type specific effects on pituitary cells (Labeur et al., 2010). BMP4 signalling was determined to stimulate proliferation and MYC expression in pituitary prolactinomas but not in other pituitary tumors, along with promoting tumorigenic growth of rat GH3 cells in nude mice (Paez-Pereda et al., 2003). BMP4 expression is reduced in corticotrophinomas from Cushing's patients in comparison to normal corticotroph cells, while BMP4 treatment of mouse AtT-20 corticotroph cells showed no effect on proliferation, but transfection of the BMP4 inhibitor Noggin stimulated tumorigenic growth in nude mice (Giacomini et al., 2006).

Entity	Renal cell carcinoma (RCC)
Prognosis	Immunohistochemical analysis of RCC tumors demonstrated BMP4 overexpression in 44%, however no prognostic value could be associated with BMP4 expression (Kwak et al., 2007). BMP4 mRNA expression was significantly higher in non-clear cell RCCs than clear cell RCCs, however no association of BMP4 expression with survival was found (Markic et al., 2011).
Oncogenesis	The BMP4 promoter was hypermethylated, resulting in downregulated expression in 35% of primary RCC tumors tested (Ricketts et al., 2012).

Entity	Retinoblastoma
Oncogenesis	BMP4 signalling was intact, and exogenous treatment increased caspase-independent apoptosis in the RB1-deficient cell line WERI-Rb1, while no effect on proliferation was seen (Haubold et al., 2010).

Entity	Various cancers
Note	Numerous microarray studies indexed in Oncomine (oncomine.org) document altered expression of BMP4 in other cancers, including head and neck cancers, cervical cancers and lymphomas and sarcomas.

External links

	Nomenclature
HGNC (Hugo)	BMP4 1071
	Cards
Atlas	BMP4ID811ch14q22
Entrez_Gene (NCBI)	BMP4 652 bone morphogenetic protein 4
GeneCards (Weizmann)	BMP4
Ensembl (Hinxton)	ENSG00000125378 [Gene_View] chr14:54416455-54423554 [Contig_View] BMP4 [Vega]
AceView (NCBI)	BMP4
Genatlas (Paris)	BMP4
WikiGenes	652
SOURCE (Princeton)	NM_001202 NM_130850 NM_130851
	Genomic and cartography
GoldenPath (UCSC)	BMP4 - 14q22.2 chr14:54416455-54423554 - 14q22-q23 [Description] (hg19-Feb_2009)
Ensembl	BMP4 - 14q22-q23 [CytoView]
Mapping of homologs : NCBI	BMP4 [Mapview]
OMIM	112262 600625 607932
	Gene and transcription
Genbank (Entrez)	BC020546 BQ083000 BU683974 BX161385 BX161438
RefSeq transcript (Entrez)	NM_001202 NM_130850 NM_130851
RefSeq genomic (Entrez)	AC_000146 NC_000014 NC_018925 NG_009215 NT_026437 NW_001838111 NW_004929393
Consensus coding sequences : CCDS (NCBI)	BMP4
Cluster EST : Unigene	Hs.68879 [ NCBI ]
CGAP (NCI)	Hs.68879
Alternative Splicing : Fast-db (Paris)	GSHG0009375
Alternative Splicing Gallery	ENSG00000125378
Gene Expression	BMP4 [ NCBI-GEO ] BMP4 [ SEEK ] BMP4 [ MEM ]
	Protein : pattern, domain, 3D structure
UniProt/SwissProt	P12644 (Uniprot)
NextProt	P12644 [Medical]
With graphics : InterPro	P12644
Splice isoforms : SwissVar	P12644 (Swissvar)
Domaine pattern : Prosite (Expaxy)	TGF_BETA_1 (PS00250) TGF_BETA_2 (PS51362)
Domains : Interpro (EBI)	TGF-b_C TGF-b_N TGF-beta-rel TGFb_CS
Related proteins : CluSTr	P12644
Domain families : Pfam (Sanger)	TGF_beta (PF00019) TGFb_propeptide (PF00688)
Domain families : Pfam (NCBI)	pfam00019 pfam00688
Domain families : Smart (EMBL)	TGFB (SM00204)
DMDM Disease mutations	652
Blocks (Seattle)	P12644
Human Protein Atlas	ENSG00000125378
Peptide Atlas	P12644
HPRD	00207
IPI	IPI00292640
	Protein Interaction databases
DIP (DOE-UCLA)	P12644
IntAct (EBI)	P12644
FunCoup	ENSG00000125378
BioGRID	BMP4
InParanoid	P12644
Interologous Interaction database	P12644
IntegromeDB	BMP4
STRING (EMBL)	BMP4
	Ontologies - Pathways
Ontology : AmiGO	negative regulation of transcription from RNA polymerase II promoter activation of MAPKK activity osteoblast differentiation ureteric bud development branching involved in ureteric bud morphogenesis kidney development mesonephros development neural tube closure positive regulation of protein phosphorylation positive regulation of endothelial cell proliferation endochondral ossification blood vessel endothelial cell proliferation involved in sprouting angiogenesis chondrocyte differentiation hematopoietic progenitor cell differentiation lymphoid progenitor cell differentiation renal system process BMP signaling pathway involved in heart induction secondary heart field specification endocardial cushion development cardiac septum development type B pancreatic cell development mesenchymal to epithelial transition involved in metanephros morphogenesis cytokine activity protein binding extracellular region extracellular region proteinaceous extracellular matrix extracellular space common-partner SMAD protein phosphorylation smoothened signaling pathway germ cell development mesodermal cell fate determination growth factor activity heparin binding negative regulation of cell proliferation post-embryonic development anterior/posterior axis specification specification of organ position positive regulation of endothelial cell migration positive regulation of pathway-restricted SMAD protein phosphorylation positive regulation of pathway-restricted SMAD protein phosphorylation positive regulation of cell death telencephalon development dorsal/ventral neural tube patterning telencephalon regionalization pituitary gland development extracellular matrix organization erythrocyte differentiation monocyte differentiation macrophage differentiation positive regulation of bone mineralization BMP signaling pathway BMP signaling pathway positive regulation of BMP signaling pathway negative regulation of chondrocyte differentiation positive regulation of collagen biosynthetic process negative regulation of T cell differentiation in thymus negative regulation of immature T cell proliferation in thymus protein localization to nucleus embryonic hindlimb morphogenesis tendon cell differentiation deltoid tuberosity development chemoattractant activity negative regulation of phosphorylation odontogenesis of dentin-containing tooth odontogenesis regulation of odontogenesis of dentin-containing tooth embryonic digit morphogenesis positive regulation of apoptotic process negative regulation of apoptotic process steroid hormone mediated signaling pathway negative regulation of MAP kinase activity positive regulation of endothelial cell differentiation negative regulation of myoblast differentiation positive regulation of neuron differentiation positive regulation of osteoblast differentiation positive regulation of ossification negative regulation of cell cycle negative regulation of mitosis negative regulation of striated muscle tissue development negative regulation of transcription, DNA-dependent positive regulation of transcription, DNA-dependent positive regulation of transcription from RNA polymerase II promoter lung alveolus development intermediate mesodermal cell differentiation positive regulation of smooth muscle cell proliferation neuron fate commitment embryonic cranial skeleton morphogenesis smooth muscle tissue development branching morphogenesis of an epithelial tube positive regulation of epithelial cell proliferation negative regulation of epithelial cell proliferation positive chemotaxis regulation of smooth muscle cell differentiation cardiac muscle cell differentiation positive regulation of cardiac muscle fiber development inner ear receptor cell differentiation cloacal septation lens induction in camera-type eye embryonic skeletal joint morphogenesis cranial suture morphogenesis positive regulation of SMAD protein import into nucleus regulation of pathway-restricted SMAD protein phosphorylation SMAD protein signal transduction lung morphogenesis bronchus development trachea development trachea formation epithelial tube branching involved in lung morphogenesis branching involved in prostate gland morphogenesis bud elongation involved in lung branching epithelial cell proliferation involved in lung morphogenesis bud dilation involved in lung branching negative regulation of cell death mammary gland formation epithelial-mesenchymal cell signaling negative regulation of prostatic bud formation regulation of branching involved in prostate gland morphogenesis positive regulation of cartilage development positive regulation of branching involved in lung morphogenesis BMP signaling pathway involved in ureter morphogenesis BMP signaling pathway involved in renal system segmentation pulmonary artery endothelial tube morphogenesis negative regulation of thymocyte apoptotic process positive regulation of ERK1 and ERK2 cascade BMP receptor binding cellular response to growth factor stimulus BMP signaling pathway involved in nephric duct formation renal system development glomerular visceral epithelial cell development negative regulation of branch elongation involved in ureteric bud branching by BMP signaling pathway specification of ureteric bud anterior/posterior symmetry by BMP signaling pathway glomerular capillary formation negative regulation of glomerular mesangial cell proliferation mesenchymal cell proliferation involved in ureteric bud development mesenchymal cell differentiation involved in kidney development ureter epithelial cell differentiation ureter smooth muscle cell differentiation mesenchymal cell proliferation involved in ureter development negative regulation of mesenchymal cell proliferation involved in ureter development metanephric collecting duct development positive regulation of kidney development negative regulation of branching involved in ureteric bud morphogenesis negative regulation of glomerulus development negative regulation of metanephric S-shaped body morphogenesis negative regulation of metanephric comma-shaped body morphogenesis positive regulation of DNA-dependent DNA replication negative regulation of cell proliferation involved in heart morphogenesis
Ontology : EGO-EBI	negative regulation of transcription from RNA polymerase II promoter activation of MAPKK activity osteoblast differentiation ureteric bud development branching involved in ureteric bud morphogenesis kidney development mesonephros development neural tube closure positive regulation of protein phosphorylation positive regulation of endothelial cell proliferation endochondral ossification blood vessel endothelial cell proliferation involved in sprouting angiogenesis chondrocyte differentiation hematopoietic progenitor cell differentiation lymphoid progenitor cell differentiation renal system process BMP signaling pathway involved in heart induction secondary heart field specification endocardial cushion development cardiac septum development type B pancreatic cell development mesenchymal to epithelial transition involved in metanephros morphogenesis cytokine activity protein binding extracellular region extracellular region proteinaceous extracellular matrix extracellular space common-partner SMAD protein phosphorylation smoothened signaling pathway germ cell development mesodermal cell fate determination growth factor activity heparin binding negative regulation of cell proliferation post-embryonic development anterior/posterior axis specification specification of organ position positive regulation of endothelial cell migration positive regulation of pathway-restricted SMAD protein phosphorylation positive regulation of pathway-restricted SMAD protein phosphorylation positive regulation of cell death telencephalon development dorsal/ventral neural tube patterning telencephalon regionalization pituitary gland development extracellular matrix organization erythrocyte differentiation monocyte differentiation macrophage differentiation positive regulation of bone mineralization BMP signaling pathway BMP signaling pathway positive regulation of BMP signaling pathway negative regulation of chondrocyte differentiation positive regulation of collagen biosynthetic process negative regulation of T cell differentiation in thymus negative regulation of immature T cell proliferation in thymus protein localization to nucleus embryonic hindlimb morphogenesis tendon cell differentiation deltoid tuberosity development chemoattractant activity negative regulation of phosphorylation odontogenesis of dentin-containing tooth odontogenesis regulation of odontogenesis of dentin-containing tooth embryonic digit morphogenesis positive regulation of apoptotic process negative regulation of apoptotic process steroid hormone mediated signaling pathway negative regulation of MAP kinase activity positive regulation of endothelial cell differentiation negative regulation of myoblast differentiation positive regulation of neuron differentiation positive regulation of osteoblast differentiation positive regulation of ossification negative regulation of cell cycle negative regulation of mitosis negative regulation of striated muscle tissue development negative regulation of transcription, DNA-dependent positive regulation of transcription, DNA-dependent positive regulation of transcription from RNA polymerase II promoter lung alveolus development intermediate mesodermal cell differentiation positive regulation of smooth muscle cell proliferation neuron fate commitment embryonic cranial skeleton morphogenesis smooth muscle tissue development branching morphogenesis of an epithelial tube positive regulation of epithelial cell proliferation negative regulation of epithelial cell proliferation positive chemotaxis regulation of smooth muscle cell differentiation cardiac muscle cell differentiation positive regulation of cardiac muscle fiber development inner ear receptor cell differentiation cloacal septation lens induction in camera-type eye embryonic skeletal joint morphogenesis cranial suture morphogenesis positive regulation of SMAD protein import into nucleus regulation of pathway-restricted SMAD protein phosphorylation SMAD protein signal transduction lung morphogenesis bronchus development trachea development trachea formation epithelial tube branching involved in lung morphogenesis branching involved in prostate gland morphogenesis bud elongation involved in lung branching epithelial cell proliferation involved in lung morphogenesis bud dilation involved in lung branching negative regulation of cell death mammary gland formation epithelial-mesenchymal cell signaling negative regulation of prostatic bud formation regulation of branching involved in prostate gland morphogenesis positive regulation of cartilage development positive regulation of branching involved in lung morphogenesis BMP signaling pathway involved in ureter morphogenesis BMP signaling pathway involved in renal system segmentation pulmonary artery endothelial tube morphogenesis negative regulation of thymocyte apoptotic process positive regulation of ERK1 and ERK2 cascade BMP receptor binding cellular response to growth factor stimulus BMP signaling pathway involved in nephric duct formation renal system development glomerular visceral epithelial cell development negative regulation of branch elongation involved in ureteric bud branching by BMP signaling pathway specification of ureteric bud anterior/posterior symmetry by BMP signaling pathway glomerular capillary formation negative regulation of glomerular mesangial cell proliferation mesenchymal cell proliferation involved in ureteric bud development mesenchymal cell differentiation involved in kidney development ureter epithelial cell differentiation ureter smooth muscle cell differentiation mesenchymal cell proliferation involved in ureter development negative regulation of mesenchymal cell proliferation involved in ureter development metanephric collecting duct development positive regulation of kidney development negative regulation of branching involved in ureteric bud morphogenesis negative regulation of glomerulus development negative regulation of metanephric S-shaped body morphogenesis negative regulation of metanephric comma-shaped body morphogenesis positive regulation of DNA-dependent DNA replication negative regulation of cell proliferation involved in heart morphogenesis
Pathways : BIOCARTA	ALK in cardiac myocytes [Genes]
Pathways : KEGG	TGF-beta signaling pathway Hedgehog signaling pathway
REACTOME	BMP4
Protein Interaction Database	BMP4
Wikipedia pathways	BMP4
	Gene fusion - rearrangments
	Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)	BMP4
SNP (GeneSNP Utah)	BMP4
SNP : HGBase	BMP4
Genetic variants : HAPMAP	BMP4
1000_Genomes	BMP4
ICGC program	ENSG00000125378
Somatic Mutations in Cancer : COSMIC	BMP4
CONAN: Copy Number Analysis	BMP4
Mutations and Diseases : HGMD	BMP4
OMIM	112262 600625 607932
GENETests	BMP4
Disease Genetic Association	BMP4
Huge Navigator	BMP4 [HugePedia] BMP4 [HugeCancerGEM]
Genomic Variants	BMP4 BMP4 [DGVbeta]
Exome Variant	BMP4
dbVar	BMP4
ClinVar	BMP4
snp3D : Map Gene to Disease	652
	General knowledge
Homologs : HomoloGene	BMP4
Homology/Alignments : Family Browser (UCSC)	BMP4
Phylogenetic Trees/Animal Genes : TreeFam	BMP4
Chemical/Protein Interactions : CTD	652
Chemical/Pharm GKB Gene	PA25381
Clinical trial	BMP4
Cancer Resource (Charite)	ENSG00000125378
	Other databases
Other database	PhosphoSitePlus
	Probes
	Litterature
PubMed	271 Pubmed reference(s) in Entrez
CoreMine	BMP4
iHOP	BMP4

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Bone morphogenetic protein-4 inhibits proliferation and induces apoptosis of multiple myeloma cells.

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Transcriptional activation of BMP-4 and regulation of mammalian organogenesis by GATA-4 and -6.

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Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT116 cells.

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Bone morphogenetic protein-4 inhibits heat-induced apoptosis by modulating MAPK pathways in human colon cancer HCT116 cells.

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Bone morphogenetic protein 4 induces epithelial-mesenchymal transition through MSX2 induction on pancreatic cancer cell line.

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Expression of bone morphogenetic proteins, the subfamily of the transforming growth factor-beta superfamily, in renal cell carcinoma.

Kwak C, Park YH, Kim IY, Moon KC, Ku JH.

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Bone morphogenetic protein-4 abrogates lumen formation by mammary epithelial cells and promotes invasive growth.

Montesano R.

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Functional implication of BMP4 expression on angiogenesis in malignant melanoma.

Rothhammer T, Bataille F, Spruss T, Eissner G, Bosserhoff AK.

Oncogene. 2007 Jun 14;26(28):4158-70. Epub 2006 Dec 18.

PMID 17173062

BMP4 induces EMT and Rho GTPase activation in human ovarian cancer cells.

Theriault BL, Shepherd TG, Mujoomdar ML, Nachtigal MW.

Carcinogenesis. 2007 Jun;28(6):1153-62. Epub 2007 Feb 1.

PMID 17272306

Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways.

Bakrania P, Efthymiou M, Klein JC, Salt A, Bunyan DJ, Wyatt A, Ponting CP, Martin A, Williams S, Lindley V, Gilmore J, Restori M, Robson AG, Neveu MM, Holder GE, Collin JR, Robinson DO, Farndon P, Johansen-Berg H, Gerrelli D, Ragge NK.

Am J Hum Genet. 2008 Feb;82(2):304-19. doi: 10.1016/j.ajhg.2007.09.023. Epub 2008 Jan 31.

PMID 18252212

Bone morphogenetic proteins 1 to 7 in human breast cancer, expression pattern and clinical/prognostic relevance.

Davies SR, Watkins G, Douglas-Jones A, Mansel RE, Jiang WG.

J Exp Ther Oncol. 2008;7(4):327-38.

PMID 19227012

Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer.

Houlston RS, Webb E, Broderick P, Pittman AM, Di Bernardo MC, Lubbe S, Chandler I, Vijayakrishnan J, Sullivan K, Penegar S; Colorectal Cancer Association Study Consortium, Carvajal-Carmona L, Howarth K, Jaeger E, Spain SL, Walther A, Barclay E, Martin L, Gorman M, Domingo E, Teixeira AS; CoRGI Consortium, Kerr D, Cazier JB, Niittymaki I, Tuupanen S, Karhu A, Aaltonen LA, Tomlinson IP, Farrington SM, Tenesa A, Prendergast JG, Barnetson RA, Cetnarskyj R, Porteous ME, Pharoah PD, Koessler T, Hampe J, Buch S, Schafmayer C, Tepel J, Schreiber S, Volzke H, Chang-Claude J, Hoffmeister M, Brenner H, Zanke BW, Montpetit A, Hudson TJ, Gallinger S; International Colorectal Cancer Genetic Association Consortium, Campbell H, Dunlop MG.

Nat Genet. 2008 Dec;40(12):1426-35. doi: 10.1038/ng.262. Epub 2008 Nov 16.

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Bone morphogenetic protein-4 strongly potentiates growth factor-induced proliferation of mammary epithelial cells.

Montesano R, Sarkozi R, Schramek H.

Biochem Biophys Res Commun. 2008 Sep 12;374(1):164-8. doi: 10.1016/j.bbrc.2008.07.007. Epub 2008 Jul 14.

PMID 18625198

Role of the transcriptional corepressor Bcor in embryonic stem cell differentiation and early embryonic development.

Wamstad JA, Corcoran CM, Keating AM, Bardwell VJ.

PLoS One. 2008 Jul 30;3(7):e2814. doi: 10.1371/journal.pone.0002814.

PMID 18795143

Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development.

Zhao H, Ayrault O, Zindy F, Kim JH, Roussel MF.

Genes Dev. 2008 Mar 15;22(6):722-7. doi: 10.1101/gad.1636408.

PMID 18347090

A predicted functional single-nucleotide polymorphism of bone morphogenetic protein-4 gene affects mRNA expression and shows a significant association with cutaneous melanoma in Southern Italian population.

Capasso M, Ayala F, Russo R, Avvisati RA, Asci R, Iolascon A.

J Cancer Res Clin Oncol. 2009 Dec;135(12):1799-807. doi: 10.1007/s00432-009-0628-y. Epub 2009 Jun 26.

PMID 19557432

Identification of an ancient Bmp4 mesoderm enhancer located 46 kb from the promoter.

Chandler KJ, Chandler RL, Mortlock DP.

Dev Biol. 2009 Mar 15;327(2):590-602. doi: 10.1016/j.ydbio.2008.12.033. Epub 2009 Jan 3.

PMID 19159624

Overexpression of bone morphogenetic protein 4 enhances the invasiveness of Smad4-deficient human colorectal cancer cells.

Deng H, Ravikumar TS, Yang WL.

Cancer Lett. 2009 Aug 28;281(2):220-31. doi: 10.1016/j.canlet.2009.02.046. Epub 2009 Mar 24.

PMID 19321257

Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2.

Gordon KJ, Kirkbride KC, How T, Blobe GC.

Carcinogenesis. 2009 Feb;30(2):238-48. doi: 10.1093/carcin/bgn274. Epub 2008 Dec 4.

PMID 19056927

DNA methylation markers predict outcome in node-positive, estrogen receptor-positive breast cancer with adjuvant anthracycline-based chemotherapy.

Hartmann O, Spyratos F, Harbeck N, Dietrich D, Fassbender A, Schmitt M, Eppenberger-Castori S, Vuaroqueaux V, Lerebours F, Welzel K, Maier S, Plum A, Niemann S, Foekens JA, Lesche R, Martens JW.

Clin Cancer Res. 2009 Jan 1;15(1):315-23. doi: 10.1158/1078-0432.CCR-08-0166.

PMID 19118060

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Contributor(s)

Written	12-2012	Brigitte L Thériault, Mark W Nachtigal
		Division of Applied Molecular Oncology, Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada (BLT); Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada (MWN)

Citation
This paper should be referenced as such :
Thériault BL, Nachtigal MW . BMP4 (bone morphogenetic protein 4). Atlas Genet Cytogenet Oncol Haematol. December 2012 .

URL : http://AtlasGeneticsOncology.org/Genes/BMP4ID811ch14q22.html

The various updated versions of this paper are referenced and archived by INIST as such :

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indexed on : Thu Feb 6 13:05:38 CET 2014

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