Eylem Seç
The Role of Nuclear Localization and Nic-Protein Complex Formation in Notch Induced Neoplasia
Başlık:
The Role of Nuclear Localization and Nic-Protein Complex Formation in Notch Induced Neoplasia
Yazar:
Jeffries, Shawn, author.
ISBN:
9780438023222
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (207 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Anil Menon.
Özet:
Notch genes encode a family of single pass transmembrane receptors that mediate important cell-fate decisions such as differentiation, proliferation and apoptosis through direct intercellular contact. Signaling is initiated when ligand, expressed on an adjacent cell, binds to the extracellular domain of the Notch receptor. This event initiates a series of proteolytic processing events of the Notch receptor at the plasma membrane, which ultimately results in release of the Notch intracellular domain (Nic) into the cytoplasm. Nic it thought to then translocate into the nucleus and alter gene expression through direct interaction with the transcriptional repressor CSL. Nic is believed to displace CSL co-repressors and to recruit additional coactivators, such as proteins of the Mastermind gene family. Substantial evidence indicates that mammalian Notch genes can act as potent oncogenes, however the mechanism by which expression of Notch transforms cells is still unknown. Previously we demonstrated that expression of N1ic could induce neoplastic transformation of E1A immortalized baby rat kidney cells (RKE). Utilizing the RKE transformation assay we report direct evidence that Nic must accumulate within the nucleus to induce transformation. Additionally, we mapped the minimal domain of Nic required for neoplastic transformation. We find that Nic exists in a high-molecular-weight protein complex with both CSL and Mastermind-Like-1 (Maml-1) in the nucleus of Nic-transformed RKE cells and in a human leukemia cell line. Formation of this complex is required for both Nic-mediated transactivation and transformation, as Nic mutants defective in complex assembly can no longer transform RKE cells nor induce gene activation. In our study we further explore the role of Maml-1 in Notch activation and complex assembly. We find that the C-terminus of Maml-1 contains a transcriptional activation domain that is required to promote transactivation of Nic. This domain, in concert with the N-terminus of Maml-1, interacts with the general coactivator p300. Furthermore, we find that p300 can acetylate Maml-1 and that this event increases Nic/CSL/Maml-1 complex formation on DNA in vitro. Thus these studies represent an initial characterization of the molecular mechanisms involved in Nic-induced neoplastic transformation.
Notlar:
School code: 0045
Konu Başlığı:
Tüzel Kişi Ek Girişi:
Mevcut:*
Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(684113.1) | 684113-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
On Order
Liste seç
Bunu varsayılan liste yap.
Öğeler başarıyla eklendi
Öğeler eklenirken hata oldu. Lütfen tekrar deneyiniz.
:
Select An Item
Data usage warning: You will receive one text message for each title you selected.
Standard text messaging rates apply.