Frequent activation of CArG binding factor-A expression and binding in N-methyl-N-nitrosourea-induced rat mammary carcinomas.
We previously identified a positive transcriptional element identical to human Ha-ras response element (HRE) within the promoter of the rat Ha-ras gene. We further identified CArG binding factor A (CBF-A), a member of heterogeneous nuclear ribonuclear protein (hnRNP) gene family, as a trans-acting factor that binds the HRE sequence with high affinity in rat mammary carcinoma cells. To determine if activation of CBF-A plays a role in tumor development in vivo , we investigated CBF-A expression and binding activity in rat mammary tumors induced by N-methyl-N-nitrosourea. We found that approximately 82% of tumors expressed CBF-A at levels that were 3-20 fold higher than detected in normal mammary gland. Moreover, elevated CBF-A protein levels were invariably associated with increased binding activity to the HRE. CBF-A mRNA levels in tumors were on average elevated only two fold as compared to normal mammary gland, indicating that increased CBF-A protein levels in tumors resulted from both translational and/or post-translational regulation. The level of CBF-A expression in mammary tumors was independent of Ha-ras mutational status. Together, these findings indicated that deregulation of CBF-A contributes to mammary carcinogenesis via a mechanism that is distinct from its hnRNP functions in binding and post-transcriptional regulation of RNA.
Mikheev
Andrei M
AM
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. amikheev@fhcrc.org
Inoue
Akira
A
Jing
Lichen
L
Mikheeva
Svetlana A
SA
Li
Vivian
V
Leanderson
Tomas
T
Zarbl
Helmut
H
D000477:Alkylating Agents / Q000008:administration & dosage; D000818:Animals; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000096:biosynthesis* / Q000494:pharmacology*; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology*; D008770:Methylnitrosourea / Q000008:administration & dosage; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000494:pharmacology*; D012261:Ribonucleoproteins; D014157:Transcription Factors
D000477:Alkylating Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C121363:Hnrnpab protein, rat; D012333:RNA, Messenger; D012097:Repressor Proteins; D012261:Ribonucleoproteins; D014157:Transcription Factors; D008770:Methylnitrosourea