Orphan nuclear receptor PNR/NR2E3 stimulates p53 functions by enhancing p53 acetylation.
Since inactivation of tumor suppressor p53 functions is one of the most common features of human cancer cells, restoring p53 expression and activity is an important focus in cancer therapy. Here we report identification of photoreceptor-specific nuclear receptor (PNR)/NR2E3 as a positive regulator of p53 in a high-throughput genetic screen. In HeLa cells, PNR stimulated p53-responsive promoters in a p53-dependent fashion and induced apoptosis in several cell types. PNR also increased p53 protein stability and specific activity as a transcriptional activator. Our studies of the underlying mechanisms showed that PNR forms complexes with p53 and the acetyltransferase p300, stimulates p53 acetylation, and increases the expression of a subset of p53 target genes. Furthermore, PNR significantly boosted actinomycin D-stimulated p53 acetylation. The unique mechanisms by which PNR stimulates p53 acetylation and functions define this orphan nuclear receptor as a potentially valuable target and tool in p53-associated cancer therapy and offer new insights into the roles of PNR mutation in retinal diseases.
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Zhi
Z
Wen
Dohun
D
Pyeon
Yidan
Y
Wang
Paul
P
Lambert
Wei
W
Xu
Paul
P
Ahlquist
D000107:Acetylation; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D003609:Dactinomycin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D000903:Antibiotics, Antineoplastic; D003609:Dactinomycin; D057093:Orphan Nuclear Receptors; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C403073:NR2E3 protein, human