Interaction of Nkx3.1 and p27kip1 in prostate tumor initiation.
The homeodomain transcription factor Nkx3.1 and the cyclin-dependent kinase inhibitor p27kip1 have both been implicated in prostate tumor suppression. In addition, both of these molecules demonstrate haploinsufficiency for tumor suppression, in which loss of a single allele is sufficient to lead to the development of preneoplastic or neoplastic lesions. We have generated mice carrying compound mutant alleles of Nkx3.1 and p27 to explore the roles of these factors in prostate tumorigenesis. Our results indicate that Nkx3.1 and p27kip1 cooperate to suppress the proliferation of prostatic epithelial cells and the formation of preneoplastic lesions resembling prostatic intraepithelial neoplasia. Cooperativity was most evident with complete loss of at least one of the two genes because compound heterozygous mice exhibited a prostatic phenotype that was no more severe than that of single heterozygous mutants. Thus Nkx3.1 and p27kip1 regulate prostatic epithelial cell proliferation and tumor initiation by affecting both haploinsufficient and nonhaploinsufficient pathways.
Gary
Bernard
B
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA.
Azuero
Ricardo
R
Mohanty
Gayatree S
GS
Bell
Walter C
WC
Eltoum
Isam-Eldin A
IE
Abdulkadir
Sarki A
SA
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004847:Epithelial Cells / Q000166:cytology; D005838:Genotype; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism*; D010641:Phenotype; D011467:Prostate / Q000166:cytology / Q000473:pathology; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; C102837:Nkx3-1 protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27