PMID- 8246958
OWN - NLM
STAT- MEDLINE
DCOM- 19940103
LR  - 20210526
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 13
IP  - 12
DP  - 1993 Dec
TI  - Activation of the mouse mdr3 gene by insertion of retroviruses in 
      multidrug-resistant P388 tumor cells.
PG  - 7380-92
AB  - In multidrug-resistant (MDR) derivatives of the mouse lymphoid tumor P388, the 
      emergence of MDR is associated with overexpression and transcriptional activation 
      of the mdr3 gene, either in the absence of (P388/VCR-10) or concomitant with 
      (P388/ADM-2) gene amplification. In both instances, Northern (RNA) blotting 
      analyses have suggested the presence of altered mdr3 transcripts in these cells, 
      possibly originating from novel transcription initiation sites. The mechanisms 
      underlying mdr3 overexpression in these cells have been investigated. In 
      P388/VCR-10 cells, Southern blotting analyses together with genomic DNA cloning 
      and nucleotide sequencing have demonstrated the presence of an intact mouse 
      mammary tumor virus (MMTV) within the boundaries of intron 1 of mdr3. cDNA 
      cloning and nucleotide sequencing indicated that this integration event results 
      in the synthesis and overexpression of a hybrid MMTV-mdr3 mRNA which initiates 
      within the U3 region of the 5' long terminal repeat (LTR) of the provirus. 
      Consequently, this mRNA lacks the normal exon 1 of mdr3 but contains (i) MMTV 
      LTR-derived sequences at its 5' end, (ii) a novel mdr3 exon, mapping within the 
      boundaries of intron 1 downstream of the MMTV integration site and generated by 
      alternative splicing, and (iii) an otherwise intact 3' portion of mdr3 starting 
      at exon 2. A similar type of analysis of P388/ADM-2 cells revealed that mdr3 
      overexpression in these cells is associated with the integration of an 
      intracisternal A particle (IAP) within an L1Md repetitive element, immediately 
      upstream of mdr3. The IAP insertion results in the overexpression of hybrid 
      IAP-mdr3 mRNA transcripts that initiate within the 3' LTR of the IAP and which 
      contain IAP LTR-derived sequences at the 5' end spliced 14 nucleotides upstream 
      of the normal exon 1 of mdr3. Taken together, these results indicate that 
      independent retroviral insertions were the initial mutagenic event responsible 
      for mdr3 overexpression and survival during drug selection of these cell lines. 
      Amplification of the rearranged and activated mdr3 gene copy occurred during 
      further selection for high-level drug resistance in P388/ADM-2 cells.
FAU - Lepage, P
AU  - Lepage P
AD  - Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
FAU - Devault, A
AU  - Devault A
FAU - Gros, P
AU  - Gros P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (DNA, Neoplasm)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Neoplasm)
SB  - IM
GS  - mdr3
MH  - Animals
MH  - Base Sequence
MH  - Chromosome Mapping
MH  - Cloning, Molecular
MH  - DNA, Neoplasm/genetics
MH  - Drug Resistance/*genetics
MH  - Enhancer Elements, Genetic
MH  - *Gene Expression Regulation, Neoplastic
MH  - Gene Rearrangement
MH  - Leukemia P388/*genetics
MH  - Lysogeny/genetics
MH  - Mammary Tumor Virus, Mouse/*genetics
MH  - Mice
MH  - Molecular Sequence Data
MH  - Promoter Regions, Genetic
MH  - Proviruses/genetics
MH  - RNA, Messenger/genetics
MH  - RNA, Neoplasm/genetics
MH  - Transcriptional Activation
MH  - Tumor Cells, Cultured/drug effects
PMC - PMC364809
EDAT- 1993/12/01 00:00
MHDA- 1993/12/01 00:01
PMCR- 1993/12/01
CRDT- 1993/12/01 00:00
PHST- 1993/12/01 00:00 [pubmed]
PHST- 1993/12/01 00:01 [medline]
PHST- 1993/12/01 00:00 [entrez]
PHST- 1993/12/01 00:00 [pmc-release]
AID - 10.1128/mcb.13.12.7380-7392.1993 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1993 Dec;13(12):7380-92. doi: 10.1128/mcb.13.12.7380-7392.1993.