RREB-1, a novel zinc finger protein, is involved in the differentiation response to Ras in human medullary thyroid carcinomas.
An activated ras oncogene induces a program of differentiation in the human medullary thyroid cancer cell line TT. This differentiation process is accompanied by a marked increase in the transcription of the human calcitonin (CT) gene. We have localized a unique Ras-responsive transcriptional element (RRE) in the CT gene promoter. DNase I protection indicates two domains of protein-DNA interaction, and each domain separately can confer Ras-mediated transcriptional inducibility. This bipartite RRE was also found to be Raf responsive. By affinity screening, we have cloned a cDNA coding for a zinc finger transcription factor (RREB-1) that binds to the distal RRE. The consensus binding site for this factor is CCCCAAACCACCCC. RREB-1 is expressed ubiquitously in human tissues outside the adult brain. Overexpression of RREB-1 protein in TT cells confers the ability to mediate increased transactivation of the CT gene promoter-reporter construct during Ras- or Raf-induced differentiation. These data suggest that RREB-1 may play a role in Ras and Raf signal transduction in medullary thyroid cancer and other cells.
Thiagalingam
A
A
Oncology Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
De Bustros
A
A
Borges
M
M
Jasti
R
R
Compton
D
D
Diamond
L
L
Mabry
M
M
Ball
D W
DW
Baylin
S B
SB
Nelkin
B D
BD
D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002116:Calcitonin / Q000096:biosynthesis* / Q000235:genetics; D018276:Carcinoma, Medullary; D002454:Cell Differentiation; D002460:Cell Line; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D003850:Deoxyribonuclease I; D004958:Estradiol / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D013964:Thyroid Neoplasms; D014157:Transcription Factors / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C101743:RREB1 protein, human; D011994:Recombinant Proteins; D014157:Transcription Factors; D004958:Estradiol; D002116:Calcitonin; D003850:Deoxyribonuclease I