RBBP9 Human
Description
Molecular Structure and Catalytic Activity
RBBP9 belongs to the α/β hydrolase family and contains a conserved catalytic triad (Ser75, His165, Asp138), which defines its serine hydrolase activity . Structural studies reveal a mixed α-helix/β-sheet architecture with an LxCxE motif critical for RB binding . While its substrates remain undefined, RBBP9’s enzymatic activity is essential for suppressing TGF-β-mediated antiproliferative signaling .
Experimental Evidence
Modulation of RB/E2F Pathway
RBBP9 competes with E2F1 for RB binding, displacing E2F1 and enabling cell cycle gene expression. This interaction is independent of its hydrolase activity .
Role in Diverse Cancers
RBBP9 is implicated in multiple malignancies through mechanisms beyond TGF-β regulation:
Interactions and Functional Partners
RBBP9 interacts with key regulators of cell cycle and chromatin structure:
Key Interacting Proteins
Small-Molecule Inhibitors
ML114, a selective RBBP9 serine hydrolase inhibitor, disrupts proliferation in human pluripotent stem cells (hPSCs) without inducing differentiation .
Preclinical Findings
| Target | Effect of Inhibition | Model | Source |
|---|---|---|---|
| RBBP9 SH Activity | Reduced cell cycle progression in hPSCs | Human embryonic stem cells | |
| TGF-β Signaling | Increased Smad2/3 phosphorylation | Pancreatic carcinoma cells |
Synthetic Lethality in Fanconi Anemia (FA)-Deficient Cancers
RBBP9 knockdown selectively kills FA-deficient HNSCC cells, offering a potential therapeutic strategy for FA-associated cancers .
Intestinal Inflammation and Tumorigenesis
RBBP9 deficiency exacerbates colitis and colitis-associated cancer (CAC) by upregulating interferon signaling and epithelial apoptosis .
Key Findings
| Model | Observation | Source |
|---|---|---|
| DSS-Induced Colitis | Rbbp9−/− mice show enhanced inflammation and tumorigenesis | |
| Organoid Experiments | RBBP9 inhibits STAT1-dependent apoptosis in intestinal epithelium |
Pluripotency Maintenance
RBBP9 supports hPSC self-renewal by regulating cell cycle genes (e.g., NFYA) independently of differentiation .
Clinical Relevance and Challenges
While preclinical data highlight RBBP9 as a therapeutic target, challenges include:
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Substrate Identification: Lack of defined enzymatic targets complicates drug development.
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Tissue-Specific Roles: Context-dependent functions (e.g., tumor-promoting vs. inflammation-suppressing) require nuanced therapeutic approaches.
Product Specs
Product Science Overview
Retinoblastoma Binding Protein 9 (RBBP9) is a protein encoded by the RBBP9 gene in humans. This protein is known for its interaction with the retinoblastoma protein (pRB), which plays a crucial role in regulating the cell cycle and preventing uncontrolled cell proliferation. The recombinant form of this protein is produced through genetic engineering techniques, allowing for its use in various research and therapeutic applications.
RBBP9 is involved in several cellular processes, primarily through its interaction with the retinoblastoma protein (pRB). The pRB protein is a well-known tumor suppressor that regulates the cell cycle by controlling the transition from the G1 phase to the S phase . RBBP9 binds to pRB, influencing its ability to regulate cell proliferation and differentiation .
One of the key functions of RBBP9 is its role in the regulation of cell population proliferation. It has been shown to affect cell-cycle control and confer transforming ability, which means it can induce changes in cell behavior that may lead to tumorigenesis . Additionally, RBBP9 has hydrolase activity, which allows it to participate in various biochemical reactions within the cell .
Mutations or dysregulation of the RBBP9 gene have been associated with several diseases, including retinoblastoma and certain types of cataracts . Retinoblastoma is a malignant tumor of the retina that primarily affects young children. The interaction between RBBP9 and pRB is critical in understanding the molecular mechanisms underlying this disease .
The recombinant form of RBBP9 is produced using genetic engineering techniques, which involve inserting the RBBP9 gene into a suitable expression system, such as bacteria or yeast. This allows for the large-scale production of the protein for research and therapeutic purposes.
In research, recombinant RBBP9 is used to study its interactions with other proteins, its role in cell cycle regulation, and its involvement in tumorigenesis. Understanding these interactions can provide insights into the development of new therapeutic strategies for diseases associated with RBBP9 dysregulation .
