Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclin-dependent kinase (CDK) inhibitor p27/Kip1 (p27) is a diagnostic and prognostic marker of various malignancies. Low expression of p27 reflects poor differentiation and poor prognosis, and an inverse correlation between the expression of p27 and degree of tumor malignancy has been reported. Because p27 mutation is extremely rare in human tumors, it is important to study the expression of p27 and its inactivator, p38/Jab1 (JAB1). Here we analyzed the expression of p27 and JAB1 by immunohistochemistry in embryonal rhabdomyosarcoma (E-RMS). We first confirmed the expression of p27 and JAB1 in normal human tonsillar epithelium, and observed a coordinated expression pattern depending on cell differentiation. Subsequently, specimens of eight poorly- and three well-differentiated E-RMS were examined for the expression of p27 and JAB1. The analyses revealed that four out of eight poorly-differentiated E-RMS were negative for p27, with positivity for nuclear JAB (NJAB) (- / + for p27/NJAB) in three and negativity for any JAB-1 expression ( - / -) in one. The remaining four poorly-differentiated E-RMS expressed p27 in the nuclei, together with predominant NJAB (+ / +). In three well-differentiated E-RMS, only one expressed nuclear p27 and all of these three expressed no NJAB (+ / - for p27/NJAB), but expressed predominant cytoplasmic JAB1 (CJAB). These findings suggest that JAB1 may play an important role in determining the differentiation stage of rhabdomyosarcoma cells by modulating the activity of CDK inhibitor p27.
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PMID:Expression of cyclin-dependent kinase inhibitor p27/Kip1 and AP-1 coactivator p38/Jab1 correlates with differentiation of embryonal rhabdomyosarcoma. 1235 53

The Hedgehog-regulated transcription factors GLI1 and GLI2 play overlapping roles in development and disease; however, the mechanisms underlying their interplay remain elusive. We report for the first time that GLI1 and GLI2 physically and functionally interact in cancer cells. GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells. Mapping analysis demonstrated that the zinc finger domains of both proteins are required for their heteromerization. RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells, whereas PTCH1 expression was only inhibited by GLI1 depletion. qPCR screening of a large set of putative canonical and non-canonical Hedgehog/GLI targets identified further genes (e.g. E2F1, BMP1, CDK2) strongly down-regulated by GLI1 and/or GLI2 depletion in PANC1 cells, and demonstrated that ANO1, AQP1 and SOCS1 are up-regulated by knockdown of either GLI1 or GLI2. Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. Together, these findings indicate that GLI1 and GLI2 co-ordinately regulate the transcription of some genes, and provide mechanistic insight into the roles of GLI proteins in carcinogenesis.
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PMID:GLI1/GLI2 functional interplay is required to control Hedgehog/GLI targets gene expression. 3276 32