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Indirect and direct disruption of transcriptional regulation in cancer: E2F and AML-1
1Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Abstract:
The disruption of transcriptional regulatory circuits through the elimination of negative regulatory factors (tumor suppressors), the activation of positive acting factors (oncogenes), or when chimeric proteins result from chromosomal translocations, is likely a key event in multistep tumorigenesis. Here, using the transcription factors E2F and AML-1 as model systems, we discuss the disruption of coordinate transcriptional regulation in oncogenesis. E2F oncogenic signals are released when the pRb tumor suppressor is inactivated, and E2F activation may necessitate the coordinate inactivation of a second tumor suppressor, p53. AML-1 is the target of the (8;21) translocation, found in approximately 15% of acute myeloid leukemia (AML) cases, and the t(12;21), found in up to 30% of childhood B-cell acute lymphoblastic leukemias. The t(8;21) creates a fusion protein between AML-1 and a gene of unknown function, mtg8 (ETO), whereas the t(12;21) fuses the TEL (translocation-ets-leukemia) transcription factor to the N-terminus of AML-1. The inv(16), which is the most frequent anomaly found in AML, also targets AML-1, by fusing the gene that encodes AML-1's heterodimeric partner CBF beta to the smooth muscle myosin heavy chain gene MYHll. Thus, E2F and AML-1 provide excellent models for the disruption of transcriptional regulation in cancer.
Insights
Disruptions in transcriptional regulation, involving tumor suppressors and oncogenes, are key to cancer development. This study examines E2F and AML-1 transcription factors as models for understanding oncogenesis and transcriptional dysregulation.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Multistep tumorigenesis involves disruptions in transcriptional regulatory circuits.
- These disruptions include the loss of tumor suppressors, activation of oncogenes, and formation of chimeric proteins via chromosomal translocations.
Purpose of the Study:
- To discuss the disruption of coordinate transcriptional regulation in oncogenesis.
- To use transcription factors E2F and AML-1 as model systems for studying oncogenesis.
Main Methods:
- Analysis of E2F pathway involving pRb and p53 tumor suppressors.
- Examination of AML-1 gene alterations in hematologic malignancies, including specific chromosomal translocations and inversions.
Main Results:
- E2F oncogenic signals are released upon pRb inactivation, potentially requiring p53 inactivation.
- AML-1 is targeted by specific translocations (t(8;21), t(12;21)) and inversions (inv(16)) in acute myeloid leukemia and acute lymphoblastic leukemia.
- These genetic alterations create fusion proteins (e.g., AML-1/ETO, TEL/AML-1) or disrupt essential partners (CBF beta/MYH11), leading to dysregulated transcription.
Conclusions:
- E2F and AML-1 serve as valuable model systems for investigating the disruption of transcriptional regulation in cancer.
- Understanding these mechanisms is crucial for advancing cancer research and therapeutic strategies.