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Updated: May 15, 2026
Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog
Published on: November 5, 2014
STOP gene Phactr4 is a tumor suppressor
Nicole L Solimini1, Anthony C Liang, Chunxiao Xu
1Department of Genetics, Harvard University Medical School, Boston, MA 02115, USA.
Abstract:
Cancer develops through genetic and epigenetic alterations that allow unrestrained proliferation and increased survival. Using a genetic RNAi screen, we previously identified hundreds of suppressors of tumorigenesis and/or proliferation (STOP) genes that restrain normal cell proliferation. Our STOP gene set was significantly enriched for known and putative tumor suppressor genes. Here, we report a tumor-suppressive role for one STOP gene, phosphatase and actin regulator 4 (PHACTR4). Phactr4 is one of four members of the largely uncharacterized Phactr family of protein phosphatase 1 (PP1)-and actin-binding proteins. Our work suggests that Phactr4 restrains normal cell proliferation and transformation. Depletion of Phactr4 with multiple shRNAs leads to increased proliferation and soft agar colony formation. Phactr4 acts, in part, through an Rb-dependent pathway, because Rb phosphorylation is maintained upon growth factor withdrawal in Phactr4-depleted cells. Examination of tumor copy number analysis and sequencing revealed that PHACTR4 is significantly deleted and mutant in many tumor subtypes. Furthermore,cancer cell lines with reduced Phactr4 expression exhibit tumor suppressor hypersensitivity upon Phactr4 complementation,leading to reduced proliferation, transformation, and tumor formation. Thus, Phactr4 acts as a tumor suppressor that is deleted and mutant in several cancers.
Insights
Phosphatase and actin regulator 4 (PHACTR4) restrains cell proliferation and acts as a tumor suppressor. PHACTR4 is frequently deleted or mutated in various cancers, highlighting its role in preventing tumor development.
Area of Science:
- Molecular biology
- Cancer research
- Genetics
Background:
- Cancer arises from genetic and epigenetic changes enabling uncontrolled cell growth and survival.
- A prior RNAi screen identified hundreds of suppressors of tumorigenesis and/or proliferation (STOP) genes.
- The STOP gene set was enriched for known and putative tumor suppressor genes.
Purpose of the Study:
- To investigate the tumor-suppressive role of the STOP gene, phosphatase and actin regulator 4 (PHACTR4).
- To explore the mechanism by which PHACTR4 restrains cell proliferation and transformation.
Main Methods:
- Conducted genetic RNAi screening to identify STOP genes.
- Utilized shRNAs to deplete Phactr4 and assess its impact on cell proliferation and soft agar colony formation.
- Examined Phactr4's role in an Rb-dependent pathway.
- Analyzed tumor copy number and sequencing data for PHACTR4 alterations.
- Complemented Phactr4-depleted cancer cell lines to evaluate tumor suppressor activity.
Main Results:
- Depletion of Phactr4 increased cell proliferation and soft agar colony formation.
- Phactr4 depletion maintained Rb phosphorylation upon growth factor withdrawal, indicating partial Rb-dependent function.
- PHACTR4 was found to be significantly deleted and mutated across multiple tumor subtypes.
- Restoring Phactr4 expression in cancer cell lines reduced proliferation, transformation, and tumor formation.
Conclusions:
- PHACTR4 functions as a tumor suppressor by restraining normal cell proliferation.
- PHACTR4 is frequently altered (deleted or mutated) in various human cancers.
- Phactr4's tumor-suppressive activity is partly mediated through an Rb-dependent pathway.
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