Isoform- and dose-sensitive feedback interactions between paired box 6 gene and delta-catenin in cell differentiation and death.
Pax6, a mammalian homolog of the Drosophila paired box gene family member expressed in stem and progenitor cells, resides at the top of the genetic hierarchy in controlling cell fates and morphogenesis. While Pax6 activation can lead to mitotic arrest, premature neurogenesis, and apoptosis, the underlying molecular mechanisms have not been resolved. Here we report that either Pax6(+5a) or Pax6(-5a) was sufficient to promote, whereas their knockdown reduced the expression of delta-catenin (CTNND2), a neural specific member of the armadillo/beta-catenin superfamily. Pax6(+5a) elicited stronger effects on delta-catenin than Pax6(-5a). Inducible Pax6(+5a) expression demonstrated a biphasic and dose-dependent regulation of delta-catenin expression and cell fates. A moderate upregulation of Pax6(+5a) promoted delta-catenin expression and induced neurite-like cellular protrusions, but increasing expression of Pax6(+5a) reversed these processes. Furthermore, sustained high expression of Pax6(+5a) triggered apoptosis as determined by the reduction of phospho-Bad, Bcl-2, survivin and procaspases, as well as the increases in Bax and cleaved poly(ADP-ribose) polymerase. Importantly, re-introducing delta-catenin by ectopic expression elicited a feedback suppression on Pax6(+5a) expression and reduced Pax6(+5a) induced apoptosis. Therefore, delta-catenin expression is not only controlled by Pax6, but it also provides a feedback suppression mechanism for their functional interactions with important implications in cellular morphogenesis, apoptosis, and cancer.
Zhang
Jiao
J
Department of Hematology and Oncology, Southeast University School of Clinical Medicine, Nanjing, China.
Lu
Jian-Ping
JP
Suter
David M
DM
Krause
Karl-Heinz
KH
Fini
M Elizabeth
ME
Chen
Baoan
B
Lu
Qun
Q
D000818:Animals; D051177:Catenins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D016923:Cell Death / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000095002:Delta Catenin
D051177:Catenins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D020033:Protein Isoforms; D012097:Repressor Proteins; D000095002:Delta Catenin