Complex functions of mutant p53 alleles from human prostate cancer.
BACKGROUND
Few studies have used multiple assays to examine the functionality of mutant p53 in prostate cancer (CaP). We employed seven functional assays to study 16 representative mutant p53 alleles, six from localized and ten from metastatic CaP.


METHODS
Yeast assays were employed to determine loss of function (LOF), partial function (PF), and dominant-negative status. Assays using p53-null Saos2 cells were used to determine whether mammalian cells transfected with mutant p53 could up-regulate the MDR-1 or PCNA promoters, alter IL-6 expression or confer the ability to grow in soft agar. As a further test of gain of function (GOF), p53-null PC3 cells stably transfected with these mutant p53 alleles were examined for cell cycle distributions.


RESULTS
All 16 mutant p53 alleles demonstrated either total or partial LOF. All but one allele also had at least one gain of function; however, the pattern of GOF was different for each mutant allele. Alleles derived from both localized and metastatic CaP had similar GOF characteristics; however, only alleles from metastatic disease had significantly increased S-phase fractions.


CONCLUSIONS
Different mutant p53 alleles from CaP had different, complex functional profiles. The lack of predictable patterns for these alleles suggest that each mutation may uniquely affect p53 function.
Shi
Xu-Bao
XB
Department of Urology, University of California, Davis, School of Medicine, Sacramento, California 95817, USA.
Nesslinger
Nancy J
NJ
Deitch
Arline D
AD
Gumerlock
Paul H
PH
deVere White
Ralph W
RW
D000483:Alleles; D015153:Blotting, Western; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D005434:Flow Cytometry; D016158:Genes, p53 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016196:S Phase / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins