Canonical Wnt/β-catenin signaling drives human schwann cell transformation, progression, and tumor maintenance.

نویسندگان

  • Adrienne L Watson
  • Eric P Rahrmann
  • Branden S Moriarity
  • Kwangmin Choi
  • Caitlin B Conboy
  • Andrew D Greeley
  • Amanda L Halfond
  • Leah K Anderson
  • Brian R Wahl
  • Vincent W Keng
  • Anthony E Rizzardi
  • Colleen L Forster
  • Margaret H Collins
  • Aaron L Sarver
  • Margaret R Wallace
  • Stephen C Schmechel
  • Nancy Ratner
  • David A Largaespada
چکیده

Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identified several genes involved in canonical Wnt signaling as potential drivers of benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofibromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with downregulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, R-spondin 2 (RSPO2). Induction of Wnt signaling was sufficient to induce transformed properties in immortalized human Schwann cells, and downregulation of this pathway was sufficient to reduce the tumorigenic phenotype of human MPNST cell lines. Small-molecule inhibition of Wnt signaling effectively reduced the viability of MPNST cell lines and synergistically induced apoptosis when combined with an mTOR inhibitor, RAD-001, suggesting that Wnt inhibition represents a novel target for therapeutic intervention in Schwann cell tumors.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Interaction of viral oncogenic proteins with the Wnt signaling pathway

It is estimated that up to 20% of all types of human cancers worldwide are attributed to viruses. The genome of oncogenic viruses carries genes that have protein products that act as oncoproteins in cell proliferation and transformation. The modulation of cell cycle control mechanisms, cellular regulatory and signaling pathways by oncogenic viruses, plays an important role in viral carcinogenes...

متن کامل

The Canonical Wnt Signaling (Wnt/β-Catenin Pathway): A Potential Target for Cancer Prevention and Therapy

Precise regulation of signal transduction pathways is crucial for normal animal development and for maintaining cellular and tissue homeostasis in adults. The Wnt/Frizzled-mediated signaling includes canonical and non-canonical signal transduction pathways. Upregulation or downregulation of the canonical Wnt-signaling (or the Wnt/β-Catenin signal transduction) leads to a variety of human diseas...

متن کامل

Beta-catenin Forms Protein Aggregation at High Concentrations in HEK293TCells

Background: The canonical Wnt signal transduction (or the Wnt/β-catenin pathway) plays a crucial role in the development of animals and in carcinogenesis. Beta-catenin is the central component of this signaling pathway. The activation of Wnt/β-catenin signaling results in the cytoplasmic and nuclear accumulation of β-catenin. In the nucleus, β-catenin interacts with the TCF/LEF transcription fa...

متن کامل

Canonical Wnt/b-catenin Signaling Drives Human Schwann Cell Transformation, Progression, and Tumor Maintenance

Adrienne L. Watson 1,2,4,5 , Eric P. Rahrmann 1,2,4,5 , Branden S. Moriarity 1,2,4,5 , Kwangmin Choi 8,10 , Caitlin B. Conboy 1 , Andrew D. Greeley 1,2 , Amanda L. Halfond 6 , Leah K. Anderson 2 , Brian R. Wahl 2 , Vincent W. Keng 1,2,4,5,13 , Anthony E. Rizzardi 3,12 , Colleen L. Forster 7 , Margaret H. Collins9,10, Aaron L. Sarver 1 , Margaret R. Wallace 11 , Stephen C. Schmechel 3,7,12 , Nan...

متن کامل

The Role of Wnt/β-catenin Signaling Pathway in Rat Primordial Germ Cells Reprogramming and Induction into Pluripotent State

 Primordial Germ Cells (PGCs) are unipotent precursors of the gametes. PGCs can give rise to a type of pluripotent stem cells in vitro that are called embryonic germ (EG) cells. PGCs can also acquire such pluripotency in vivo and generate teratomas. Under specific culture conditions, PGCs can be reprogrammed to embryonic germ cells which are capable of expression of key pluripotency marker...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Cancer discovery

دوره 3 6  شماره 

صفحات  -

تاریخ انتشار 2013