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Published on: June 15, 2017
Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins
A Lasorella1, M Noseda, M Beyna
1Department of Neurology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Abstract:
In mammalian cells, Id proteins coordinate proliferation and differentiation. Id2 is a dominant-negative antagonist of basic helix-loop-helix transcription factors and proteins of the retinoblastoma (Rb) family. Here we show that Id2-Rb double knockout embryos survive to term with minimal or no defects in neurogenesis and haematopoiesis, but they die at birth from severe reduction of muscle tissue. In neuroblastoma, an embryonal tumour derived from the neural crest, Id2 is overexpressed in cells carrying extra copies of the N-myc gene. In these cells, Id2 is in molar excess of the active form of Rb. The overexpression of Id2 results from transcriptional activation by oncoproteins of the Myc family. Cell-cycle progression induced by Myc oncoproteins requires inactivation of Rb by Id2. Thus, a dual connection links Id2 and Rb: during normal cell-cycle, Rb prohibits the action of Id2 on its natural targets, but oncogenic activation of the Myc-Id2 transcriptional pathway overrides the tumour-suppressor function of Rb.
Insights
Id2 and retinoblastoma (Rb) proteins regulate cell growth. While Rb normally inhibits Id2, Myc oncoproteins activate Id2, overriding Rb
Area of Science:
- Cell biology
- Molecular oncology
- Developmental biology
Background:
- Id proteins are key regulators of cell proliferation and differentiation in mammals.
- Id2 acts as a dominant-negative inhibitor of basic helix-loop-helix transcription factors and retinoblastoma (Rb) proteins.
- Dysregulation of Id2 and Rb interactions is implicated in cellular processes and cancer.
Purpose of the Study:
- To investigate the functional relationship between Id2 and Rb in mammalian development and cancer.
- To elucidate the role of Id2 in neuroblastoma, particularly in relation to N-myc amplification.
- To understand how Myc oncoproteins influence the Id2-Rb axis.
Main Methods:
- Generation and analysis of Id2-Rb double knockout mouse embryos.
- Investigation of Id2 expression and Rb interaction in neuroblastoma cell lines with varying N-myc copy numbers.
- Analysis of transcriptional regulation of Id2 by Myc family oncoproteins.
Main Results:
- Id2-Rb double knockout embryos exhibit normal neurogenesis and haematopoiesis but die at birth due to severe muscle tissue reduction.
- Id2 is overexpressed in neuroblastoma cells with extra N-myc gene copies, where Id2 exceeds active Rb.
- Myc oncoproteins transcriptionally activate Id2, and this pathway is crucial for Myc-induced cell-cycle progression via Rb inactivation.
Conclusions:
- Id2 and Rb have a dual regulatory relationship, with Rb normally opposing Id2's action.
- Oncogenic activation of the Myc-Id2 pathway overrides the tumor-suppressive function of Rb, highlighting a critical mechanism in neuroblastoma development.
- The Id2-Rb axis is essential for normal muscle development and its dysregulation contributes to oncogenesis.
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