| 1. |
- An, Jiabin, et al.
(författare)
-
Inactivation of the CYLD Deubiquitinase by HPV E6 Mediates Hypoxia-Induced NF-kappa B Activation
- 2008
-
Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 14:5, s. 394-407
-
Tidskriftsartikel (refereegranskat)abstract
- The biochemical mechanisms that underlie hypoxia-induced NF-kappa B activity have remained largely undefined. Here, we find that prolonged hypoxia-induced NF-kappa B activation is restricted to cancer cell lines infected with high-risk human papillomavirus (HPV) serotypes. The HPV-encoded E6 protein is necessary and sufficient for prolonged hypoxia-induced NF-kappa B activation in these systems. The molecular target of E6 in the NF-kappa B pathway is the CYLD lysine 63 (K63) deubiquitinase, a negative regulator of the NF-kappa B pathway. Specifically, hypoxia stimulates E6-mediated ubiquitination and proteasomal degradation of CYLD. Given the established role of NF-kappa B in human carcinogenesis, these findings provide a potential molecular/viral link between hypoxia and the adverse clinical outcomes observed in HPV-associated malignancies.
|
|
| 2. |
|
|
| 3. |
- Bereshchenko, Oxana, et al.
(författare)
-
Hematopoietic Stem Cell Expansion Precedes the Generation of Committed Myeloid Leukemia-initiating Cells in C/EBP alpha Mutant AML
- 2009
-
Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 16:5, s. 390-400
-
Tidskriftsartikel (refereegranskat)abstract
- We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia. We find that C-terminal C/EBP alpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and override normal HSC homeostasis, leading to expansion of premalignant HSCs. However, such mutations impair myeloid programming of HSCs and block myeloid lineage commitment when homozygous. In contrast, N-terminal C/EBP alpha mutations are silent with regards to HSC expansion, but allow the formation of committed myeloid progenitors, the templates for leukemia-initiating cells. The combination of N- and C-terminal C/EBP alpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Kirstetter, Peggy, et al.
(författare)
-
Modeling of C/EBP alpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells
- 2008
-
Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 13:4, s. 299-310
-
Tidskriftsartikel (refereegranskat)abstract
- Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBP alpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1(+)c-Kit(+) population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1(+)c-Kit(+) progenitors revealed a signature shared with MLL-AF9-transformed AML.
|
|
| 9. |
|
|
| 10. |
|
|
