DNAJC24 Human

What is DNAJC24 and what are its alternative nomenclatures?

DNAJC24 is a member of the DNAJ/HSP40 family of heat shock proteins, which are highly conserved proteins found across diverse organisms. It is also known by several alternative names including DPH4, JJJ3, and ZCSL3 . The gene is protein-coding and found in Homo sapiens with the Entrez Gene ID 120526 . As a heat shock protein family member, it plays roles in protein folding and cellular stress responses, but has more specific functions in certain biochemical pathways.

What is the basic biological function of DNAJC24?

DNAJC24 (also known as DPH4) is involved in the synthesis of diphthamide, a unique posttranslationally modified histidine found exclusively in translation elongation factor-2 (EEF2) . This modification is evolutionarily conserved from archaebacteria to humans and serves as the target for ADP-ribosylation and inactivation of EEF2 by bacterial toxins such as diphtheria toxin and Pseudomonas exotoxin A . More recent research has revealed its potential roles beyond diphthamide synthesis, particularly in cancer progression through interactions with PCNA and activation of the PI3K/AKT signaling pathway .

How is DNAJC24 expression regulated under normal physiological conditions?

While the provided search results don't specifically address the regulation of DNAJC24 under normal physiological conditions, we can infer from research on other HSP40 family members that its expression may be regulated by cellular stress responses, heat shock factors, and developmental programs. The evolutionary analysis in Japanese flounder suggests that the gene has been under strong negative selection pressure, indicating its functional importance across species . The subcellular localization analysis suggests that like many HSP40 genes, DNAJC24 may function primarily in the nucleus of cells .

How is DNAJC24 expression altered in cancer tissues compared to normal tissues?

Research demonstrates that DNAJC24 exhibits upregulated expression in lung adenocarcinoma (LUAD) tissue samples compared to normal tissues . This upregulation appears to be clinically significant as it correlates with poor survival outcomes in LUAD patients . Similarly, previous studies have found that DNAJC24 was closely associated with the malignant phenotype of hepatocellular carcinoma, suggesting its potential role in multiple cancer types . This pattern of overexpression aligns with observations for other heat shock proteins, as many HSP family members are overexpressed in various tumors and widely involved in oncogenesis, tumor development, and therapeutic resistance .

What cellular phenotypes are affected by DNAJC24 in cancer progression?

Experimental evidence indicates that upregulation of DNAJC24 expression promotes proliferation and invasion of LUAD cells, as demonstrated in A549 and NCI-H1299 cell lines . This suggests that DNAJC24 contributes to two key hallmarks of cancer: sustained proliferative signaling and activated invasion. The protein appears to play an important role in the malignant phenotypic transformation of LUAD cells, potentially contributing to disease progression and metastatic potential . These findings position DNAJC24 as a significant contributor to the aggressive behavior of lung adenocarcinoma.

What is the prognostic significance of DNAJC24 expression in cancer patients?

DNAJC24 upregulation predicts poor survival in LUAD patients, indicating its potential value as a prognostic biomarker . The correlation between DNAJC24 expression levels and clinical outcomes suggests that it could serve as a specific prognostic biomarker for LUAD patients, potentially helping to stratify patients for more personalized treatment approaches . This prognostic significance adds to the growing body of evidence supporting the clinical relevance of heat shock proteins in cancer biology and patient management.

How does DNAJC24 regulate cellular signaling pathways?

Studies have revealed that DNAJC24 regulates the PI3K/AKT signaling pathway by affecting AKT phosphorylation . The PI3K/AKT pathway is a critical signaling cascade involved in cell survival, proliferation, and metabolism, and its dysregulation is implicated in various cancers. By promoting AKT phosphorylation, DNAJC24 likely enhances the activation of downstream effectors that contribute to malignant transformation and cancer progression . This mechanism positions DNAJC24 as a potential upstream regulator of a key oncogenic pathway.

What protein interactions has DNAJC24 been shown to participate in?

A series of experiments including co-immunoprecipitation (Co-IP) and mass spectrometry have confirmed that DNAJC24 can directly interact with Proliferating Cell Nuclear Antigen (PCNA) . PCNA is a critical factor in DNA replication, repair, and cell cycle regulation. The direct interaction between DNAJC24 and PCNA suggests a potential role for DNAJC24 in these fundamental cellular processes . This interaction appears to be functionally significant, as it promotes the malignant phenotypic transformation of LUAD cells .

How does the DNAJC24/PCNA/AKT axis contribute to cancer progression?

The DNAJC24/PCNA/AKT axis represents a molecular pathway that connects DNAJC24's interaction with PCNA to the activation of AKT signaling . Research suggests that DNAJC24 binding to PCNA somehow facilitates AKT phosphorylation, though the exact molecular mechanisms linking these events require further investigation . This signaling axis contributes to the malignant progression of LUAD by promoting cell proliferation and invasion . The identification of this axis provides a conceptual framework for understanding how DNAJC24 contributes to cancer progression and offers potential targets for therapeutic intervention.

What experimental techniques are effective for studying DNAJC24-PCNA interactions?

Based on the search results, several experimental approaches have proven effective for studying DNAJC24-PCNA interactions:

• Co-immunoprecipitation (Co-IP): This technique was successfully used to demonstrate the direct interaction between DNAJC24 and PCNA proteins .

• Mass spectrometry: Following Co-IP, mass spectrometry analysis helped confirm the interaction and potentially identify other components of the protein complex .

• Cell line models: A549 and NCI-H1299 lung adenocarcinoma cell lines have been effectively used to study DNAJC24 function and interactions .

• Expression manipulation: Modulating DNAJC24 expression levels through overexpression or knockdown approaches can help establish the functional significance of its interaction with PCNA .

• Phosphorylation assays: Western blotting with phospho-specific antibodies can be used to assess how DNAJC24-PCNA interaction affects AKT phosphorylation status .

What approaches can be used to investigate DNAJC24's role in AKT phosphorylation?

Researchers investigating DNAJC24's role in AKT phosphorylation can employ several methodological approaches:

• Phosphorylation analysis: Western blotting using antibodies specific for phosphorylated AKT at key residues (particularly Ser473 and Thr308) can directly measure the effect of DNAJC24 manipulation on AKT activation .

• Kinase inhibition studies: Using specific inhibitors of the PI3K/AKT pathway in combination with DNAJC24 manipulation can help position where in the signaling cascade DNAJC24 exerts its effects .

• Downstream target analysis: Examining the phosphorylation status of AKT substrates (such as GSK3β, FOXO proteins, or mTOR components) can provide insights into the functional consequences of DNAJC24-mediated AKT activation .

• Proximity ligation assays: These can help determine whether DNAJC24 directly interacts with components of the PI3K/AKT pathway or if the effect is mediated through its interaction with PCNA.

• Domain mapping and mutagenesis: Generating mutant versions of DNAJC24 can help identify which domains are critical for its effects on AKT phosphorylation.

What cell and tissue models are most appropriate for DNAJC24 functional studies?

The search results provide guidance on suitable models for DNAJC24 research:

• Human lung adenocarcinoma cell lines: A549 and NCI-H1299 have been successfully used to study DNAJC24 function in the context of lung cancer .

• Human tissue samples: LUAD tissue samples compared with adjacent normal lung tissue provide valuable clinical context for DNAJC24 expression studies .

• Hepatocellular carcinoma models: Given the previous association of DNAJC24 with hepatocellular carcinoma, liver cancer cell lines and tissues may also be appropriate models .

• Comparative models: While focusing on human DNAJC24, insights from studies in other species (such as the Japanese flounder) might provide evolutionary context and functional conservation information .

How might DNAJC24 serve as a therapeutic target for cancer treatment?

The DNAJC24/PCNA/AKT axis presents a potential target for future individualized and precise treatment of LUAD patients . Several therapeutic approaches could be considered:

• Direct DNAJC24 inhibition: Developing small molecules or peptides that inhibit DNAJC24 function could potentially reduce cancer cell proliferation and invasion.

• Disruption of DNAJC24-PCNA interaction: Compounds that specifically interfere with the binding between DNAJC24 and PCNA could inhibit the downstream activation of AKT signaling.

• Combination approaches: Targeting DNAJC24 in combination with existing PI3K/AKT pathway inhibitors might enhance therapeutic efficacy and reduce resistance mechanisms.

• DNAJC24-based immunotherapies: Given its elevated expression in cancer tissues, DNAJC24 could potentially serve as a target for cancer immunotherapy approaches.

What are the potential biomarker applications of DNAJC24 in cancer diagnosis and prognosis?

DNAJC24 shows promise as a biomarker in several contexts:

• Prognostic biomarker: The correlation between DNAJC24 upregulation and poor survival in LUAD patients suggests its utility as a prognostic indicator .

• Predictive biomarker: Further research may establish whether DNAJC24 expression levels can predict response to specific therapies, particularly those targeting the PI3K/AKT pathway.

• Diagnostic biomarker: The differential expression between cancer and normal tissues suggests potential diagnostic applications, especially if DNAJC24 elevation can be detected in minimally invasive samples.

• Treatment monitoring: Changes in DNAJC24 expression levels during treatment could potentially serve as a marker of therapeutic response.

How conserved is DNAJC24 across species and what does this suggest about its function?

Research on the hsp40 gene family in Japanese flounder provides some insights into the evolutionary conservation of DNAJC24:

• Evolutionary constraint: Analysis of dN/dS ratios for hsp40 genes, including dnajc24, indicates pronounced negative selection, suggesting functional conservation across species .

• Subcellular localization: Most hsp40 genes, potentially including DNAJC24, appear to function in the nucleus of cells across different species .

• Response to stressors: In Japanese flounder, dnajc24 gene expression was affected by bacterial infection (E. tarda), suggesting a potential role in stress response that may be conserved across species .

• Structural conservation: The functional domains of DNAJC24 likely show conservation across species, reflecting its important role in basic cellular processes .

The evolutionary conservation of DNAJC24 suggests that it performs fundamental cellular functions that have been maintained throughout evolution, while its dysregulation in human cancers represents a pathological alteration of these conserved functions.