TY - JOUR
T1 - AKT and PAX3-FKHR cooperation enforces myogenic differentiation blockade in alveolar rhabdomyosarcoma cell
AU - Jothi, Mathivanan
AU - Nishijo, Kochi
AU - Keller, Charles
AU - Mal, Asoke K.
N1 - Funding Information:
microsystems). This work was supported by Public Health Service grant Primers and oligonucleotide. Primers for cloning AR051502 to A.K.M. from National Institute of Arthritis and 6XPRS-9 binding sites: Forward: CCG CTC GAG CGG Musculoskeletal and Skin Diseases (NIAMS). We would like to ATC GAT AAT TCG AGC TCG AC; Reverse: TCC CCC thank Frederic G. Barr (Laboratory of Pathology, National Cancer GGG GGA GCC CAA GGT CGA AGC TTA Institute) and Eugene Kandel (Roswell Park Cancer Institute) for GFP: Forward: AAC TGC AGA ACC AAT GCA TTG GAT providing reagents. We would also like to thank Munmun Mal GGT GAG CAA GGG C; Reverse: CGG GAT CCC GTT for experimental assistance and Catherine Burkhart (Cleveland ACT TGT ACA GCT CGT CCA TG BioLabs) for discussion and comments on the manuscript.
PY - 2012/3/1
Y1 - 2012/3/1
N2 - The chimeric PAX3-FKHR transcription factor is present in a majority of alveolar rhabdomyosarcoma (ARMS), an aggressive skeletal muscle cancer of childhood. PAX3-FKHR-mediated aberrant myogenic gene expression resulting in escape from terminal differentiation program is believed to contribute in ARMS development. In skeletal muscle differentiation, activation of AKT pathway leads to myogenic gene activation and terminal differentiation. Here, we report that AKT acts, in part, by modulating PAX3-FKHR transcriptional activity via phosphorylation in the maintenance of the myogenic differentiation blockade in established mouse models of ARMS cells. We observed that low levels of AKT activity are associated with elevated levels of PAX3-FKHR transcriptional activity, and AKT hyperactivation results in PAX3-FKHR phosphorylation coupled with decreased activity once cells are under differentiation-permissible conditions. Subsequent data shows that attenuated AKT activity-associated PAX3-FKHR activity is required to suppress the function of MyoD, a key myogenic regulator of muscle differentiation. Conversely, decreased PAX3-FKHR activity results in the eradication of MyoD expression and subsequent suppression of the myogenic differentiation. Thus, AKT regulation of the PAX3-FKHR suppresses myogenic gene expression in ARMS cells, causing a failure in differentiation. Evidence is presented that provides a novel molecular link between AKT and PAX3-FKHR in maintaining myogenic differentiation blockade in ARMS.
AB - The chimeric PAX3-FKHR transcription factor is present in a majority of alveolar rhabdomyosarcoma (ARMS), an aggressive skeletal muscle cancer of childhood. PAX3-FKHR-mediated aberrant myogenic gene expression resulting in escape from terminal differentiation program is believed to contribute in ARMS development. In skeletal muscle differentiation, activation of AKT pathway leads to myogenic gene activation and terminal differentiation. Here, we report that AKT acts, in part, by modulating PAX3-FKHR transcriptional activity via phosphorylation in the maintenance of the myogenic differentiation blockade in established mouse models of ARMS cells. We observed that low levels of AKT activity are associated with elevated levels of PAX3-FKHR transcriptional activity, and AKT hyperactivation results in PAX3-FKHR phosphorylation coupled with decreased activity once cells are under differentiation-permissible conditions. Subsequent data shows that attenuated AKT activity-associated PAX3-FKHR activity is required to suppress the function of MyoD, a key myogenic regulator of muscle differentiation. Conversely, decreased PAX3-FKHR activity results in the eradication of MyoD expression and subsequent suppression of the myogenic differentiation. Thus, AKT regulation of the PAX3-FKHR suppresses myogenic gene expression in ARMS cells, causing a failure in differentiation. Evidence is presented that provides a novel molecular link between AKT and PAX3-FKHR in maintaining myogenic differentiation blockade in ARMS.
KW - AKT
KW - Alveolar rhabdomyosarcoma
KW - Muscle differentiation
KW - Myogenic regulator MyoD
KW - PAX3-FKHR
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UR - http://www.scopus.com/inward/citedby.url?scp=84857982296&partnerID=8YFLogxK
U2 - 10.4161/cc.11.5.19346
DO - 10.4161/cc.11.5.19346
M3 - Article
C2 - 22333587
AN - SCOPUS:84857982296
SN - 1538-4101
VL - 11
SP - 895
EP - 908
JO - Cell Cycle
JF - Cell Cycle
IS - 5
ER -