CXCR4 Is a PAX Family Transcription Factor Regulated Gene.
Bibliographic record
Abstract
Abstract CXCR4 is a G protein-coupled receptor expressed on versatile tissue/organ specific stem cells that binds the α-chemokine SDF-1, and the PAX gene family (PAX1 – 9) encodes transcription factors that have been implicated in organogenesis and stem cell development. It has been demonstrated that the SDF-1-CXCR4 axis regulates trafficking of several types of normal early stem/progenitor cells and malignant tumor cells that derive from them. Recently our group focused on the role of CXCR4 in regulating the motility of skeletal muscle stem/progenitors and reported that it is expressed on normal skeletal muscle satellite stem cells (Stem Cells2003; 21: 363.), and is highly up-regulated on rhabdomyosarcomas (RMS) (Blood2002; 100: 2597) originating from transformed muscle satellite cells. We observed that the expression of CXCR4 correlated with the presence of PAX3 and PAX7 transcription factors (muscle satellite stem cells) and was up-regulated in RMS cells that express the more active version of PAX genes, PAX3-FKHR and PAX7-FKHR fusion proteins. Based on this we hypothesized that PAX genes regulate CXCR4 expression in normal muscle satellite stem cells and their more active fusion-gene counterparts are responsible for up-regulation of CXCR4 in RMS. To better address this issue, we first compared CXCR4 expression by real-time RT-PCR and FACS in several human RMS cells lines and found that expression of CXCR4 correlated with the more metastatic, alveolar subtype of RMS and a better responsiveness to SDF-1. Second, sequence analysis of the CXCR4 promoter revealed several putative PAX gene binding sites (ATTA and GTNNN motifs) at −658–672, −696–709, −737–758, −809–821, −1580–1610, −1693–1697, −1853–1857, −1865–1879, −1937–1946, −2195–2199 and −2297–2302 bp of the reported CXCR4 promoter sequence. Third, to evaluate whether PAX regulates the expression of CXCR4, a 2335 bp upstream fragment of the human CXCR4 promoter gene or its shorter fragments (1819 bp, 1547 bp, 850 bp, 528 bp and 106 bp) were subcloned into a CAT basic reporter gene plasmid and assayed in cells expressing or not expressing the PAX3-FKHR fusion gene. We observed that the CAT activity of all promoter fragments except the 1547 bp fragment was significantly enhanced in cells transduced with the PAX3-FKHR expression vector, what suggests the presence of a negative regulatory element in addition to several positive regulatory PAX binding domains. No promoter activity was observed with the smallest 106 bp fragment. Finally, chromatin immunoprecipitation (ChIP) assay revealed that the PAX3-FKHR protein binds to the CXCR4 promoter. Thus, we provide evidence that expression of CXCR4 is regulated by PAX transcription regulatory factors. Furthermore, we postulate that various PAX proteins that bind to similar DNA consensus sequences may regulate CXCR4 expression in various early normal stem/progenitor cells in a tissue-specific manner (e.g., PAX 1 in osteoblastic progenitors, PAX 3 in neural-crest and skeletal muscle progenitors, PAX 5 in B lymphocytes, PAX 6 in endocrine pancreatic progenitors, PAX 7 in skeletal muscle satellite cells, etc.), what is crucial for proper trafficking of these cells during organogenesis. Furthermore, the potential deregulation of PAX genes in tumor cells leads to overexpression of CXCR4, enhanced responsiveness to SDF-1 and metastasis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.010 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".