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Id2 promotes apoptosis by a novel mechanism independent of dimerization to basic helix-loop-helix factors
M Florio1, M C Hernandez, H Yang
1Preuss Laboratory for Molecular Neuro-Oncology, Brain Tumor Research Center, Department of Neurological Surgery, University of California, San Francisco, California 94143-0520, USA.
Abstract:
Members of the helix-loop-helix (HLH) family of Id proteins have demonstrated roles in the regulation of differentiation and cell proliferation. Id proteins inhibit differentiation by HLH-mediated heterodimerization with basic HLH transcription factors. This blocks their sequence-specific binding to DNA and activation of target genes that are often expressed in a tissue-specific manner. Id proteins can also act as positive regulators of cell proliferation. The different mechanisms proposed for Id-mediated promotion of entry into S phase also involve HLH-mediated interactions affecting regulators of the G1/S transition. We have found that Id2 augments apoptosis in both interleukin-3 (IL-3)-dependent 32D.3 myeloid progenitors and U2OS osteosarcoma cells. We could not detect a similar activity for Id3. In contrast to the effects of Id2 on differentiation and cell proliferation, Id2-mediated apoptosis is independent of HLH-mediated dimerization. The ability of Id2 to promote cell death resides in its N-terminal region and is associated with the enhanced expression of a known component of the programmed cell death pathway, the proapoptotic gene BAX.
Insights
The Id2 protein promotes apoptosis, a programmed cell death pathway, in myeloid progenitors and osteosarcoma cells. This cell death-promoting activity is independent of its helix-loop-helix (HLH) domain interactions.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Biology
Background:
- Members of the helix-loop-helix (HLH) family of Id proteins regulate cell differentiation and proliferation.
- Id proteins inhibit differentiation and promote proliferation through HLH-mediated interactions with basic HLH transcription factors.
- These interactions affect DNA binding and target gene activation, influencing cell cycle progression.
Purpose of the Study:
- To investigate the role of Id proteins, specifically Id2 and Id3, in regulating apoptosis.
- To determine the mechanisms underlying Id2-mediated apoptosis, including its dependence on HLH interactions.
- To identify regions of Id2 responsible for inducing cell death.
Main Methods:
- Utilized interleukin-3 (IL-3)-dependent 32D.3 myeloid progenitors and U2OS osteosarcoma cells.
- Assessed the effects of Id2 and Id3 expression on apoptosis.
- Investigated the role of HLH-mediated dimerization in Id2-induced apoptosis.
- Analyzed the N-terminal region of Id2 for cell death-promoting activity.
- Examined the expression of the proapoptotic gene BAX.
Main Results:
- Id2 was found to augment apoptosis in both 32D.3 myeloid progenitors and U2OS osteosarcoma cells.
- Id3 did not exhibit similar apoptosis-augmenting activity.
- Id2-mediated apoptosis was independent of HLH-mediated dimerization, distinguishing it from its effects on differentiation and proliferation.
- The cell death-promoting ability of Id2 was localized to its N-terminal region.
- Id2 expression was associated with enhanced expression of the proapoptotic gene BAX.
Conclusions:
- Id2 functions as an inducer of apoptosis in specific cell types, independent of its canonical HLH-mediated regulatory functions.
- The N-terminal region of Id2 is critical for its proapoptotic activity.
- Id2-mediated apoptosis involves the upregulation of BAX, a key component of the programmed cell death pathway.