Article

PAX6 is expressed in pancreatic cancer and actively participates in cancer progression through activation of the MET tyrosine kinase receptor gene.

Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Journal of Biological Chemistry (impact factor: 4.77). 09/2009; 284(40):27524-32. DOI:10.1074/jbc.M109.047209 pp.27524-32
Source: PubMed

ABSTRACT Tumors of the exocrine pancreas have a poor prognosis. Several proteins are overexpressed in this cancer type, including the MET tyrosine kinase receptor and the transcription factor PAX6. In this report, we find that PAX6(5a), an alternately spliced variant form of PAX6, is expressed in pancreatic carcinoma cell lines at higher levels than the canonical PAX6 protein. Both protein forms of PAX6 bind directly to an enhancer element in the MET promoter and activate the expression of the MET gene. In addition, inhibition of PAX6 transcripts leads to a decline in cell growth and survival, differentiation, and a concurrent reduction of MET protein expression. These data support a model for a neoplastic pathway, where expression of a transcription factor from development activates the MET receptor, a protein that has been directly linked to protumorigenic processes of resisting apoptosis, tumor growth, invasion, and metastasis.

0 0
 · 
0 Bookmarks
 · 
32 Views
  • Source
    Article: Two independent and interactive DNA-binding subdomains of the Pax6 paired domain are regulated by alternative splicing.
    J A Epstein, T Glaser, J Cai, L Jepeal, D S Walton, R L Maas
    [show abstract] [hide abstract]
    ABSTRACT: Vertebrate Pax proteins share a conserved 128-amino-acid DNA-binding motif, the paired domain. The PAX6 gene, which is mutated in the murine Small eye and human aniridia developmental defects, also encodes a second protein with a 14-amino-acid insertion in the paired domain. This protein, which arises by alternative mRNA splicing, exhibits unique DNA-binding properties. Unlike other paired domains, which bind DNA predominantly by their amino termini, the extended Pax6 paired domain interacts with DNA exclusively through its carboxyl terminus. This property can be stimulated by deletion of 30 amino-terminal residues from the Pax6 or Pax2 paired domains. Thus, the insertion acts as a molecular toggle to unmask the DNA-binding potential of the carboxyl terminus. The functional nonequivalence of the two Pax6 proteins is underscored by a T-->C mutation at position -3 of the alternative splice acceptor site that changes the ratio of the two isoforms and causes a distinct human ocular syndrome.
    Genes & Development 09/1994; 8(17):2022-34. · 11.66 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

cancer type
 
canonical PAX6 protein
 
concurrent reduction
 
enhancer element
 
exocrine pancreas
 
MET gene
 
MET promoter
 
MET protein expression
 
MET receptor
 
MET tyrosine kinase receptor
 
metastasis
 
pancreatic carcinoma cell lines
 
PAX6 bind
 
PAX6 transcripts
 
poor prognosis
 
protumorigenic processes
 
transcription factor
 
transcription factor PAX6
 
tumor growth
 
Tumors
 

Joseph B Mascarenhas