Regulation and role of Brn-2 in control of Mitf expression
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- Tez No: 400881
- Danışmanlar: PROF. COLIN GODING
- Tez Türü: Doktora
- Konular: Biyokimya, Biochemistry
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2011
- Dil: İngilizce
- Üniversite: Unıversıty Of London
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: Belirtilmemiş.
Özet
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Özet (Çeviri)
One of the key issues in cancer is how signal transduction pathways regulate the transcriptional program that defines a cell's identity. In melanocytes and melanoma the Microphthalmia-associated transcription factor (Mitf) is required for melanocyte/melanoma survival, proliferation and migration/metastasis. Intermediate levels of Mitf activity promote proliferation, elevated levels of Mitf activity leads to differentiation associated with G1 arrest and high levels of p21 and p16, whereas low levels of Mitf activity leads to a p27-dependent G1 arrest and invasiveness. Understanding how Mitf expression is controlled is therefore a key issue. The Brn-2 (POU3F2) transcription factor belongs to the POU domain eukaryotic transcriptional factor family that plays a major role in development. Brn-2 is poorly expressed in melanocytes in culture, but is expressed at higher levels in melanomas. Intriguingly, Brn-2 can both activate and repress the Mitf promoter, but how Brn-2 activity is controlled is not known. We show here that the capacity of Brn-2 to activate or repress is dependent on both the target promoter and its post-translational modification. The results suggest that Alanine substitutions at phosphorylation sites at the N-terminus lead to localisation of Brn-2 to heterochromatin and failure to be phosphorylated by p38 SAPK. On the other hand, Glutamic acid substitutions lead to localisation of Brn-2 to euchromatin and enhance phosphorylation by p38 SAPK. Brn-2 is also regulated during the cell cycle. Brn-2 levels are elevated in G2 and decrease in mitosis, suggesting that Brn-2's ability to bind DNA is regulated by a mitotic kinase. In addition, we also employed a kinase inhibitor library to identify small molecule regulators of Mitf expression and found a variety of compounds that alter Mitf expression substantially. Collectively, the results indicate that regulation of Brn-2 activity may be a critical determinant of Mitf expression and consequently melanoma behaviour.
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