Reviewing the current classification of inhibitor of growth family proteins
Motoko Unoki1, Kensuke Kumamoto, Seiichi Takenoshita
1Laboratory for Biomarker, The Institute of Physical and Chemical Research, RIKEN, Tokyo, Japan.
Abstract:
Inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors for more than a decade. Recent emerging results using siRNA and knockout mice are expanding the previous understanding of this protein family. The results of ING1 knockout mouse experiments revealed that ING1 has a protective effect on apoptosis. Our recent results showed that ING2 is overexpressed in colorectal cancer, and induces colon cancer cell invasion through an MMP13-dependent pathway. Knockdown of ING2 by siRNA induces premature senescence in normal human fibroblast cells, and apoptosis or cell cycle arrest in various adherent cancer cells. Taken together, these results suggest that ING2 may also have roles in cancer progression and/or malignant transformation under some conditions. Additionally, knockdown of ING4 and ING5 by siRNA shows an inhibitory effect on the transition from G(2)/M to G(1) phase and DNA replication, respectively, suggesting that these proteins may play roles during cell proliferation in some context. ING family proteins may play dual roles, similar to transforming growth factor-beta, which has tumor suppressor-like functions in normal epithelium and also oncogenic functions in invasive metastatic cancers. In the present article, we briefly review ING history and propose a possible interpretation of discrepancies between past and recent data.
Insights
Inhibitor of growth (ING) proteins show dual roles in cancer. While ING1 protects against apoptosis, ING2 promotes colorectal cancer invasion, and other ING proteins affect cell proliferation, suggesting complex functions.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Inhibitor of growth (ING) proteins are recognized as potential tumor suppressors.
- Recent studies using siRNA and knockout models are refining the understanding of ING protein functions.
- ING family proteins are implicated in critical cellular processes, including apoptosis, cell cycle control, and proliferation.
Purpose of the Study:
- To review the history of ING proteins and reconcile conflicting data.
- To explore the multifaceted roles of ING proteins in cancer progression and malignant transformation.
- To investigate the specific roles of ING1, ING2, ING4, and ING5 in cellular processes.
Main Methods:
- Utilizing siRNA technology to knockdown ING protein expression.
- Employing knockout mouse models to study ING1 function.
- Analyzing the effects of ING protein modulation on apoptosis, cell cycle, senescence, invasion, and DNA replication.
Main Results:
- ING1 knockout mice exhibit a protective effect against apoptosis.
- ING2 overexpression correlates with colorectal cancer and promotes invasion via MMP13.
- ING2 knockdown induces senescence in normal cells and apoptosis/cell cycle arrest in cancer cells.
- ING4 and ING5 knockdown inhibit cell cycle progression and DNA replication, respectively.
Conclusions:
- ING proteins may possess dual roles, acting as tumor suppressors or oncogenes depending on the context, similar to TGF-β.
- ING2 appears to contribute to cancer progression and malignant transformation in certain conditions.
- ING family members play context-dependent roles in cell proliferation and cell fate determination.
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