Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis.
Mouse models have provided significant insights into the molecular mechanisms of tumor suppressor gene function. Here we use mouse models of prostate carcinogenesis to demonstrate that the Nkx3.1 homeobox gene undergoes epigenetic inactivation through loss of protein expression. Loss of function of Nkx3.1 in mice cooperates with loss of function of the Pten tumor suppressor gene in cancer progression. This cooperativity results in the synergistic activation of Akt (protein kinase B), a key modulator of cell growth and survival. Our findings underscore the significance of interactions between tissue-specific regulators such as Nkx3.1 and broad-spectrum tumor suppressors such as Pten in contributing to the distinct phenotypes of different cancers.
Kim
Minjung J
MJ
Center for Advanced Biotechnology and Medicine and Department of Neuroscience, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Cardiff
Robert D
RD
Desai
Nishita
N
Banach-Petrosky
Whitney A
WA
Parsons
Ramon
R
Shen
Michael M
MM
Abate-Shen
Cory
C
D000483:Alleles; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; C102837:Nkx3-1 protein, mouse; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human