BRCA1 and c-Myc associate to transcriptionally repress psoriasin, a DNA damage-inducible gene.
Evidence is accumulating to suggest that some of the diverse functions associated with BRCA1 may relate to its ability to transcriptionally regulate key downstream target genes. Here, we identify S100A7 (psoriasin), S100A8, and S100A9, members of the S100A family of calcium-binding proteins, as novel BRCA1-repressed targets. We show that functional BRCA1 is required for repression of these family members and that a BRCA1 disease-associated mutation abrogates BRCA1-mediated repression of psoriasin. Furthermore, we show that BRCA1 and c-Myc form a complex on the psoriasin promoter and that BRCA1-mediated repression of psoriasin is dependent on functional c-Myc. Finally, we show that psoriasin expression is induced by the topoisomerase IIalpha poison, etoposide, in the absence of functional BRCA1 and increased psoriasin expression enhances cellular sensitivity to this chemotherapeutic agent. Therefore, we identified a novel transcriptional mechanism that is likely to contribute to BRCA1-mediated resistance to etoposide.
Kennedy
Richard D
RD
Cancer Research Centre, Queen's University Belfast, Belfast City Hospital, Belfast, United Kingdom.
Gorski
Julia J
JJ
Quinn
Jennifer E
JE
Stewart
Gail E
GE
James
Colin R
CR
Moore
Stephen
S
Mulligan
Karl
K
Emberley
Ethan D
ED
Lioe
Tong F
TF
Morrison
Patrick J
PJ
Mullan
Paul B
PB
Reid
George
G
Johnston
Patrick G
PG
Watson
Peter H
PH
Harkin
D Paul
DP
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; D014158:Transcription, Genetic; D014162:Transfection
D000972:Antineoplastic Agents, Phytogenic; D019313:BRCA1 Protein; D002135:Calcium-Binding Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D005047:Etoposide