In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 261-261
Kurzfassung:
Oncogenesis is a complex, multi-factorial process of cellular transformation that leads to the development of many types of cancers. The factors that contribute to this process reprogram normal cellular functions, including metabolic pathways, and allow uncontrolled cell growth. The CRTC family of CREB coactivators, in conjunction with CBP/p300, cooperate in the regulation of cAMP-inducible genes involved in cell survival, proliferation, glucose metabolism, and adaptive mitochondrial biogenesis. A subset of tumors share a common t(11;19)(q21;p13.1) translocation that forms a chimeric oncogene by fusing CRTC1 to the NOTCH coactivator MAML2. Consequently, the CRTC1/MAML2 translocation induces the aberrant expression of genes regulated by CREB and NOTCH and the deregulation of these target genes is believed to cause tumorigenesis. We demonstrate that a gain-of-function activity by the CRTC1/MAML2 oncoprotein promotes interactions with the MYC:MAX network. This interaction is specific as neither CRTC1 or MAML2 parental proteins activate MYC:MAX complexes. Specifically, RNA-seq analysis revealed that a significant proporation of genes involved in key aspects of cell growth, survival, and metabolism within the MYC:MAX and CREB transcription networks are induced by CRTC1/MAML2. Analysis of cellular transformation by RK3E foci formation assays identified a synergistic effect of MYC expression on CRTC1/MAML2-induced transformation and this can be blocked by a dominant negative MYC molecule. Furthermore, in-frame deletions of CRTC1/MAML2 that lack transforming activity are unable to induce the expression of MYC-responsive reporters revealing a critical role for MYC target genes in CRTC1/MAML2-induced cell growth and transformation. Collectively, these studies indicate that CRTC1/MAML2 promotes cellular transformation through cooperative activation of MYC and CREB pathways thereby challenging current paradigms which suggest that translocations function through aberrant activation of parental pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 261. doi:10.1158/1538-7445.AM2011-261
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-261
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2011
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
