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)

A melphalan-resistant human rhabdomyosarcoma xenograft, TE-671 MR, was established in athymic mice by serial melphalan treatment of the parent xenograft, TE-671, at the 10% lethal dosage (LD10); significant resistance was evident after ten passages of the tumor. TE-671 MR demonstrated a doubling time of 3.5 days and a latency period to 1000-mm3 tumors of 27.5 days. The glutathione level of TE-671 MR was 2.36 mumol/g tumor, wet weight, 2-fold higher than the parent line. The glutathione S-transferase activity of TE-671 MR was 117.8 mumol/min/mg protein, essentially unchanged from the parent line. Although TE-671 MR demonstrated cross-resistance to vincristine, dot blot analysis did not reveal an elevated expression of mdr1 mRNA in the resistant line. TE-671 MR demonstrated a 9.7-day growth delay following treatment with melphalan at the LD10 (compared to 20.9 days for the parent line). Treatment with L-buthionine-SR-sulfoximine (BSO) resulted in increased sensitivity to melphalan subsequently administered at 50% of the LD10 (melphalan alone, growth delays of 3.7 and 4.6 days in duplicate trials; melphalan plus BSO, growth delays of 7.2 and 9.8 days). Sensitivity to melphalan equal to that of the parent line TE-671 was not achieved, however. Treatment with BSO did not result in significantly enhanced sensitivity to subsequently administered vincristine (50% of the LD10) (vincristine alone, growth delays of 6.8 and 6.9 days in duplicate trials; vincristine plus BSO, growth delays of 10.9 and 7.5 days). These results suggest that generation of melphalan resistance may be associated with development of cross-resistance to vincristine; this resistance may be associated with (although not necessarily mediated by) glutathione elevation; this resistance may be partially overcome by BSO-mediated depletion of glutathione.
 ...
PMID:Establishment of a melphalan-resistant rhabdomyosarcoma xenograft with cross-resistance to vincristine and enhanced sensitivity following buthionine sulfoximine-mediated glutathione depletion. 258 34

The polymerase chain reaction was used to amplify protein tyrosine phosphatase (PTPase)-related cDNA from a template of total RNA isolated from human skeletal muscle. A novel PTPase, which we term PTP-PEST, was detected by this method. The polymerase chain reaction fragment was used to screen two different HeLa cell libraries to obtain full length cDNA clones. The cDNA predicts a protein of 510 amino acids, approximately 60 kDa, that does not contain an obvious signal sequence or transmembrane segment suggesting it is a nonreceptor type enzyme. The PTPase domain is located in the N-terminal portion of the molecule and displays approximately 35% identity to other members of this family of enzymes. The C-terminal segment is rich in Pro, Glu, Asp, Ser, and Thr residues, possessing features of PEST motifs which have previously been identified in proteins with very short intracellular half-lives. The protein was expressed in Escherichia coli as a fusion product with glutathione S-transferase. Intrinsic activity was demonstrated in vitro against a variety of phosphotyrosine-containing substrates including BIRK, the autophosphorylated cytoplasmic kinase domain of the insulin receptor beta subunit. It did not dephosphorylate phosphoseryl-phosphorylase a. PTP-PEST mRNA is broadly distributed in a variety of cell lines. Stimulation of human rhabdomyosarcoma A204 cells, a transformed muscle line, with insulin led to an approximately 4-fold induction of PTP-PEST mRNA within 36 h.
 ...
PMID:Cloning and expression of PTP-PEST. A novel, human, nontransmembrane protein tyrosine phosphatase. 834 45

DNA topoisomerase II-an essential nuclear enzyme in DNA replication and transcription, chromatin segregation, and cell cycle progression-is also a target of clinically useful anticancer drugs. Preliminary observations of a positive correlation between the expression of topoisomerase (topo) IIalpha and the retinoblastoma protein (Rb) in a series of rhabdomyosarcoma cells prompted us to ask whether these two proteins interact in vivo. Using human rhabdomyosarcoma and leukemic cell lines, we found a physical association between topo IIalpha and Rb protein by reciprocal immunoprecipitation and immunoblotting, in which topo IIalpha appeared to interact primarily with the underphosphorylated form of Rb. Experiments with truncated glutathione S-transferase-Rb fusion proteins and nuclear extracts of Rh1 rhabdomyosarcoma cells indicated that topo IIalpha binds avidly to the A/B pocket domain of Rb, which contains the intact spacer amino acid sequence. To determine whether this interaction has functional consequences in vivo, we expressed wild-type and mutant Rb in human cervical carcinoma cells lacking functional Rb. Wild-type, but not mutant, Rb inhibited topo II activity in nuclear extracts of these transfected cells. Moreover, purified wild-type Rb inhibited the activity of purified human topo IIalpha, indicating a direct interaction between these two proteins. We conclude that topo IIalpha associates physically with Rb in interactions that appear to have functional significance.
 ...
PMID:Functional interaction between human topoisomerase IIalpha and retinoblastoma protein. 1039 12

Decidual transformation of human endometrial stromal (ES) cells requires sustained activation of the protein kinase A (PKA) pathway. In a search for novel transcriptional mediators of this process, we used differential display PCR analysis of undifferentiated primary ES cells and cells stimulated with 8-bromo-cAMP (8-Br-cAMP). We now report on the role of forkhead homologue in rhabdomyosarcoma (FKHR), a recently described member of the forkhead/winged-helix transcription factor family, as a mediator of endometrial differentiation. Sustained 8-Br-cAMP stimulation resulted in the induction and nuclear accumulation of FKHR in differentiating ES cells. Immunohistochemical studies revealed that endometrial stromal expression of FKHR in vivo is confined to decidualizing cells during the late secretory phase of the cycle and coincides with the expression of CCAAT/enhancer-binding protein beta (C/EBPbeta). Reporter gene studies showed that FKHR potently enhances PKA-dependent activation of the tissue-specific decidual prolactin (dPRL) promoter, a major differentiation marker in human ES cells. Transcriptional augmentation by FKHR was effected through functional cooperation with C/EBPbeta and binding to a composite FKHR-C/EBPbeta response unit in the proximal promoter region. Furthermore, FKHR and C/EBPbeta were shown to interact directly in a glutathione S-transferase pull-down assay. These results provide the first evidence of regulated expression of FKHR and demonstrate that FKHR has an integral role in PKA-dependent endometrial differentiation through its ability to bind and functionally cooperate with C/EBPbeta.
 ...
PMID:Cyclic AMP-induced forkhead transcription factor, FKHR, cooperates with CCAAT/enhancer-binding protein beta in differentiating human endometrial stromal cells. 1189 44