Serine Threonine Receptor-Associated Protein (STRAP) plays a role in the maintenance of mesenchymal morphology

Kashikar, Nilesh; Reiner, Jennifer Elisabeth; Datta, Arunima; Datta, Pran K.

doi:10.1016/j.cellsig.2009.09.024

Cited by 14 publications

(15 citation statements)

References 43 publications

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“…Additionally, STRAP physically interacts with PDK1 and positively modulates its downstream targets such as PKB/Akt and Bad in vivo (17). Our recent studies showed that STRAP transcriptionally downregulates E-cadherin and p21 Cip1 expressions (18), and it promotes the mesenchymal phenotype (19). …”

Section: Introductionmentioning

confidence: 99%

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

Lin

Yuan

et al. 2017

Cancer Research

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NOTCH signaling exerts essential roles in normal and malignant intestinal physiology and the homeostasis of cancer stem-like cells (CSC), but the basis for this latter role remains obscure. The signaling scaffold protein STRAP is upregulated in several cancers where it promotes tumorigenicity and metastasis. Here we report a novel oncogenic function for STRAP in maintaining CSC subpopulations in a heterogeneous mixture by antagonizing formation of the chromatin modifier PRC2 and by epigenetically activating NOTCH signals in human colorectal cancer (CRC). Silencing STRAP sensitized CRC cells to chemotherapeutic drugs in vitro and in vivo. STRAP depletion also contributed to a reduced stem-like phenotype of CRC cells, as indicated by reduced expression of the CSC signature and NOTCH signaling regulators in vitro and by diminished tumorigenesis in vivo. Genes encoding some upstream activators of NOTCH were highly enriched for H3K27me3, which form repressive chromatin domains upon STRAP silencing. Mechanistically, STRAP competitively disrupted association of the PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly. Restoring the NOTCH pathway by lentiviral expression of NICD1 or HES1 in STRAP-depleted tumor cells reversed the CSC phenotype. In 90 CRC clinical specimens, a significant positive correlation was documented between the expression of STRAP and HES1. Overall, our findings illuminated a novel STRAP-NOTCH1-HES1 molecular axis as a CSC regulator in CRC, with potential implications to improve treatment of this disease.

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Section: Introductionmentioning

confidence: 99%

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

Lin

Yuan

et al. 2017

Cancer Research

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“…[15][16] We have previously reported STRAP plays a role in maintenance of mesenchymal morphology by downregulating E-cadherin in mRNA levels, 9 which raises a possibility that STRAP might interrupt some transcription factor(s) binding to the promoter resulting in reduced transcription. So we first decided to analyze the mechanism of regulation of E-cadherin by STRAP.…”

Section: Strap Inhibits Sp1-dependent Activation Of E-cadherin Promotermentioning

confidence: 99%

“…13 We have previously reported that STRAP is involved in maintaining mesenchymal morphology by regulating E-cadherin and that it enhances tumorigenicity partly by downregulating CDK inhibitor p21 Cip1 . 9,10,12 but the functional mechanism of regulation of E-cadherin and p21…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11] There is growing evidence to suggest that STRAP exerts its tumorigenic influence on cells, largely through TGF--independent signaling. STRAP has been shown to be strong predictive marker of 5-fluorouracil-based adjuvant chemotherapy benefit in colorectal cancer and is up-regulated mostly in transformed epithelium in human colorectal and lung carcinomas.…”

Section: Introductionmentioning

confidence: 99%

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Oncogenic STRAP functions as a novel negative regulator of E-cadherin and p21^Cip1 by modulating the transcription factor Sp1

Datta¹

2014

Cell Cycle

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Abbreviations: STRAP, serine threonine kinase receptor-associated protein; Sp1, specificity protein 1; Sp/KLF, specificity protein/ Kr€ uppel-like factor; SWI/SNF, SWItch/Sucrose nonfermentable; p300/CBP, p300/ CREB-binding protein; TSS, transcription start site; MEF, mouse embryonic fibroblast; HNF4, hepatocyte nuclear factor 4; TSA, trichostatin A; HDAC1, histone deacetylase 1; HDAC2, histone deacetylase 2; HDAC3, histone deacetylase 3; NF-YA, nuclear transcription factor Y subunit alpha; TbR I, II, TGF-b receptor I, II; RNase, A ribonuclease A; CDK2, cyclin-dependent kinase 2; CDK4, cyclin-dependent kinase 4; PARP, poly (ADP-ribose) polymerase; RhoA, Ras homolog gene family, member A.We have previously reported the identification of a novel WD-domain protein, STRAP that plays a role in maintenance of mesenchymal morphology by regulating E-cadherin and that enhances tumorigenicity partly by downregulating CDK inhibitor p21 Cip1. However, the functional mechanism of regulation of E-cadherin and p21Cip1 by STRAP is unknown. Here, we have employed STRAP knock out and knockdown cell models (mouse embryonic fibroblast, human cancer cell lines) to show how STRAP downregulates E-cadherin and p21Cip1 by abrogating the binding of Sp1 to its consensus binding sites. Moreover, ChIP assays suggest that STRAP recruits HDAC1 to Sp1 binding sites in p21Cip1 promoter. Interestingly, loss of STRAP can stabilize Sp1 by repressing its ubiquitination in G1 phase, resulting in an enhanced expression of p21Cip1 by >4.5-fold and cell cycle arrest. Using Bioinformatics and Microarray analyses, we have observed that 87% mouse genes downregulated by STRAP have conserved Sp1 binding sites. In NSCLC, the expression levels of STRAP inversely correlated with that of Sp1 (60%). These results suggest a novel mechanism of regulation of E-cadherin and p21Cip1 by STRAP by modulating Sp1-dependent transcription, and higher expression of STRAP in lung cancer may contribute to downregulation of E-cadherin and p21Cip1 and to tumor progression.

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“…STRAP lacks kinase activity but has 7 WD domains, which are responsible for protein-protein interactions. There are also reports that STRAP inhibits transforming growth factor (TGF) signaling by interacting with TGF-␤ receptor and maintains the mesenchymal morphology of fibroblasts (35)(36)(37). STRAP is ubiquitously expressed, and STRAP Ϫ/Ϫ mice are embryonically lethal (38).…”

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confidence: 99%

Serine-Threonine Kinase Receptor-Associated Protein (STRAP) Regulates Translation of Type I Collagen mRNAs

Vukmirovic

Manojlovic

Stefanovic

2013

Molecular and Cellular Biology

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Type I collagen is the most abundant protein in the human body and is composed of two ␣1(I) and one ␣2(I) polypeptides which assemble into a triple helix. For the proper assembly of the collagen triple helix, the individual polypeptides must be translated in coordination. Here, we show that serine-threonine kinase receptor-associated protein (STRAP) is tethered to collagen mRNAs by interaction with LARP6. LARP6 is a protein which directly binds the 5= stem-loop (5=SL) present in collagen ␣1(I) and ␣2(I) mRNAs, but it interacts with STRAP with its C-terminal domain, which is not involved in binding 5=SL. Being tethered to collagen mRNAs, STRAP prevents unrestricted translation, primarily that of collagen ␣2(I) mRNAs, by interacting with eukaryotic translation initiation factor 4A (eIF4A). In the absence of STRAP, more collagen ␣2(I) mRNA can be pulled down with eIF4A, and collagen ␣2(I) mRNA is unrestrictedly loaded onto the polysomes. This results in an imbalance of synthesis of ␣1(I) and ␣2(I) polypeptides, in hypermodifications of ␣1(I) polypeptide, and in inefficient assembly of the polypeptides into a collagen trimer and their secretion as monomers. These defects can be partially restored by supplementing STRAP. Thus, we discovered STRAP as a novel regulator of the coordinated translation of collagen mRNAs. Collagen type I is a heterotrimeric protein composed of two ␣1 and one ␣2 polypeptides which are folded into a triple helix and secreted into the extracellular matrix (1). Type I collagen forms fibrils and provides strength and elasticity to connective tissues (2) and is normally expressed at a high level in bone, tendon, skin, and arterial adventitia (1). Fibroproliferative disorders are characterized by excessive and persistent synthesis of collagen I in parenchymal organs. Excessive deposition of type I collagen forms a fibrotic scar, resulting in organ failure. Fibroproliferative disorders are a major medical problem, associated with 45% of deaths in the United States (3, 4). Conversely, lack of type I collagen expression is incompatible with life, and an impaired ability to assemble collagen I heterotrimer leads to osteogenesis imperfecta and Ehlers-Danlos syndromes (5, 6). Currently, there is no cure for fibroproliferative diseases due to the lack of understanding of complex mechanism of collagen I biosynthesis.Expression of type I collagen is predominantly regulated at the posttranscriptional level. Stabilization of collagen mRNAs is one of the mechanisms by which collagen-producing cells increase collagen expression upon stimulation (7-13). Additionally, collagen expression is regulated by coordinating translation of collagen ␣1(I) and ␣2(I) mRNAs. Translation of collagen mRNAs is regulated by a unique structural element in the 5= untranslated regions (UTRs) of collagen mRNAs, the 5= stem-loop (5=SL) (10, 11, 14-16). La ribonucleoprotein domain family member 6 (LARP6) binds 5=SL with high affinity and specificity (17, 18). Knockdown of LARP6 or mutation of 5=SL reduces type I collagen expression a...

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Serine Threonine Receptor-Associated Protein (STRAP) plays a role in the maintenance of mesenchymal morphology

Cited by 14 publications

References 43 publications

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

Oncogenic STRAP functions as a novel negative regulator of E-cadherin and p21^Cip1 by modulating the transcription factor Sp1

Serine-Threonine Kinase Receptor-Associated Protein (STRAP) Regulates Translation of Type I Collagen mRNAs

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Serine Threonine Receptor-Associated Protein (STRAP) plays a role in the maintenance of mesenchymal morphology

Cited by 14 publications

References 43 publications

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

Oncogenic STRAP functions as a novel negative regulator of E-cadherin and p21Cip1 by modulating the transcription factor Sp1

Serine-Threonine Kinase Receptor-Associated Protein (STRAP) Regulates Translation of Type I Collagen mRNAs

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Oncogenic STRAP functions as a novel negative regulator of E-cadherin and p21^Cip1 by modulating the transcription factor Sp1