BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

Beck, Stayce E.; Jung, Barbara; Rosario, Eunice Del; Gómez, Jessica; Carethers, John M.

doi:10.1016/j.cellsig.2007.01.017

Cited by 56 publications

(47 citation statements)

References 30 publications

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“…Similar to other transforming growth factor-h (TGF-h) family members, BMPs bind cell membrane type I and II receptors of serine/threonine kinases eliciting intracellular signaling via Smad1, Smad5, Smad8 and Smad9 proteins (3,4), and the Lim kinase (5,6), and mitogenactivated protein kinase pathways (7,8). BMPs are present in cancers including breast, prostate, and colon cancers (9)(10)(11) where BMPs are implicated in regulating cancer cell proliferation (8,(12)(13)(14). BMP7 (osteogenic protein-1) is a potent inducer of cell differentiation required for vertebrate development, deletion of which is postnatal-lethal with multiple defects in differentiated tissues (15).…”

Section: Introductionmentioning

confidence: 99%

Bone Morphogenetic Protein-7 Inhibits Telomerase Activity, Telomere Maintenance, and Cervical Tumor Growth

Cassar

Pinto

et al. 2008

Cancer Research

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Telomere maintenance is critical in tumor cell immortalization. Here, we report that the cytokine bone morphogenetic protein-7 (BMP7) inhibits telomerase activity that is required for telomere maintenance in cervical cancer cells. Application of human recombinant BMP7 triggers a repression of the human telomerase reverse transcriptase (hTERT) gene, shortening of telomeres, and hTERT repression-dependent cervical cancer cell death. Continuous treatment of mouse xenograft tumors with BMP7, or silencing the hTERT gene, results in sustained inhibition of telomerase activity, shortening of telomeres, and tumor growth arrest. Overexpression of hTERT lengthens telomeres and blocks BMP7-induced tumor growth arrest. Thus, BMP7 negatively regulates telomere maintenance, inducing cervical tumor growth arrest by a mechanism of inducing hTERT gene repression. [Cancer Res 2008;68(22):9157-66]

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Section: Introductionmentioning

confidence: 99%

Bone Morphogenetic Protein-7 Inhibits Telomerase Activity, Telomere Maintenance, and Cervical Tumor Growth

Cassar

Pinto

et al. 2008

Cancer Research

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“…RAS/ERK signaling has been shown to slow or inhibit BMP-SMAD signaling when SMAD signaling is intact. 23 In a SMAD4-null environment, inhibition of the activated RAS/ERK pathway 27 with PD98059 or DN K-RAS reversed BMP-induced decreases in PTEN levels and increases in phospho-Akt. Additionally, we no longer observed the biphasic pattern or growth promotion with BMP treatment when the RAS/ERK pathway was inhibited.…”

Section: Discussionmentioning

confidence: 97%

“…Traditionally, SMAD signaling is thought of as growth suppressive for cancer development. However, there are cellular ways to modulate SMAD signaling, 23 and/or there is the existence of non-SMAD pathways that normally balance the SMAD suppressive signaling. 24 Loss of SMAD signaling would create an imbalance that could lead to growth proliferation.…”

Section: Introductionmentioning

confidence: 99%

BMP suppresses PTEN expression via RAS/ERK signaling

Beck¹,

Carethers²

2007

Cancer Biology & Therapy

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Bone morphogenetic protein (BMP), a member of the transforming growth factor β family, classically utilizes the SMAD signaling pathway for its growth suppressive effects, and loss of this signaling cascade may accelerate cell growth. In the colon cancer predisposition syndrome Juvenile Polyposis, as well as in the late progression stages of nonsyndromic colorectal cancers, SMAD4 function is typically abrogated. Here, we utilized the SMAD4-null SW480 colon cancer cell line to examine BMPs effect on a potential target gene, PTEN, and how its expression might be regulated. Initial treatment of the SMAD4-null cells with BMP resulted in mild growth suppression, but with prolonged exposure to BMP, the cells become growth stimulatory, which coincided with observed decreases in transcription and translation of PTEN, and with corresponding increases in phospho-AKT protein levels. BMP-induced PTEN suppression was mediated via the RAS/ERK pathway, as pharmacologic inhibition of RAS/ERK, or interference with protein function in the cytosol by DN-RAS prevented BMP-induced growth promotion and changes in PTEN levels, as did treatment with noggin, a BMP ligand inhibitor. Thus, BMP downregulates PTEN via RAS/ERK in a SMAD4-null environment that contributes to cell growth, and constitutes a SMAD4-independent but BMP-responsive signaling pathway.

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“…BMPs are members of the transforming growth factor beta (TGFβ) family; thus, BMPs utilize a similar signaling cascade to that of TGFβ. BMPs have been identified to utilize the SMAD signaling pathway for their growth suppressive effects, and also to affect PTEN and p21 (WAF1) expression via RAS-ERK signaling in cancer (10)(11)(12). Additionally, previous studies have revealed that genetic variations in BMP genes are associated with a number of types of cancer (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in bone morphogenetic protein 3 and the risk of papillary thyroid cancer

Kim¹,

Hong

Eun

et al. 2012

Oncology Letters

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Abstract. Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta (TGFβ) superfamily with well-described functions in bone formation. Although disrupted BMP signaling in tumor development has been investigated, a genetic association for BMP3 in papillary thyroid cancer (PTC) has remained largely unexplored. In this study, we investigated whether BMP3 single nucleotide polymorphisms (SNPs) are associated with the development of PTC and its clinicopathological features. A total of 103 PTC patients and 324 control subjects were enrolled. One promoter SNP (rs13138132; -1919C/A) and one missense mutation (rs3733549; Arg192Gln) in BMP3 were genotyped by direct sequencing. SNPStats, SNPAnalyzer, Helixtree and Haploview version 4.2 were used to evaluate the genetic data. Multiple logistic regression models were used to calculate odds ratios (ORs), 95% confidence intervals (CIs) and P-values. The missense SNP (rs3733549) was weakly associated with the development of PTC in a codominant model (AA vs. GG; P=0.017) and a recessive model (AA vs. GG/GA; P=0.023). Additionally, in an analysis according to clinicopathological features, rs13138132 was significantly associated with extrathyroidal invasion in a codominant model (CA vs. CC; P=0.006) and a dominant model (CA/AA vs. CC; P=0.0023). We also identified that the frequency of the A allele in the promoter SNP (rs13138132) was increased in PTC patients with extrathyroidal invasion (P=0.004). Our data suggest that rs3733549 in BMP3 is associated with the development of PTC and that the A allele of rs13138932 in BMP3 is a risk factor for extrathyroidal invasion. IntroductionThyroid cancer is the most common type of endocrine malignancy, accounting for approximately 1% of all cases of cancer. It is the most rapidly increasing cancer among females and the second most rapidly increasing cancer among males. Histologically, thyroid cancer is classified as papillary thyroid cancer (PTC), follicular thyroid cancer, medullary thyroid cancer or undifferentiated or anaplastic thyroid cancer. Of these, PTC is the most common type, and it accounts for 85-90% of all thyroid malignancies (1,2). Although the etiology of PTC is unclear, environmental factors, including radiation, diet, smoking and hormones, have been identified to affect the pathogenesis of thyroid cancer (3,4). Genetic predisposition has also been implicated as a risk factor for thyroid cancer development (5,6).Bone morphogenic proteins (BMPs) have been demonstrated to play an important role during development (particularly during bone formation) and in the regulation of various cellular processes, including cell proliferation, apoptosis and differentiation (7). Evidence suggests that BMPs are important in tumorigenesis (8-10). BMPs are members of the transforming growth factor beta (TGFβ) family; thus, BMPs utilize a similar signaling cascade to that of TGFβ. BMPs have been identified to utilize the SMAD signaling pathway for their growth suppressive effects, and also to affect PTEN and p21 (W...

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BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

Cited by 56 publications

References 30 publications

Bone Morphogenetic Protein-7 Inhibits Telomerase Activity, Telomere Maintenance, and Cervical Tumor Growth

Bone Morphogenetic Protein-7 Inhibits Telomerase Activity, Telomere Maintenance, and Cervical Tumor Growth

BMP suppresses PTEN expression via RAS/ERK signaling

Polymorphisms in bone morphogenetic protein 3 and the risk of papillary thyroid cancer

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