Identification of a nuclear matrix targeting signal in the leukemia and bone-related AML/CBF-alpha transcription factors.
Transcription factors of the AML (core binding factor-alpha/polyoma enhancer binding protein 2) class are key transactivators of tissue-specific genes of the hematopoietic and bone lineages. Alternative splicing of the AML-1 gene results in two major AML variants, AML-1 and AML-1B. We show here that the transcriptionally active AML-1B binds to the nuclear matrix, and the inactive AML-1 does not. The association of AML-1B with the nuclear matrix is independent of DNA binding and requires a nuclear matrix targeting signal (NMTS), a 31 amino acid segment near the C terminus that is distinct from nuclear localization signals. A similar NMTS is present in AML-2 and the bone-related AML-3 transcription factors. Fusion of the AML-1B NMTS to the heterologous GAL4-(1-147) protein directs GAL4 to the nuclear matrix. Thus, the NMTS is necessary and sufficient to target the transcriptionally active AML-1B to the nuclear matrix. The loss of the C-terminal domain of AML-1B is a frequent consequence of the leukemia-related t(8;21) and t(3;21) translocations. Our results suggest this loss may be functionally linked to the modified interrelationships between nuclear structure and gene expression characteristic of cancer cells.
Zeng
C
C
Department of Cell Biology, University of Massachusetts Medical School and Cancer Center, 55 Lake Avenue North, Worcester, MA 01655, USA.
van Wijnen
A J
AJ
Stein
J L
JL
Meyers
S
S
Sun
W
W
Shopland
L
L
Lawrence
J B
JB
Penman
S
S
Lian
J B
JB
Stein
G S
GS
Hiebert
S W
SW
D000595:Amino Acid Sequence; D001665:Binding Sites; D001842:Bone and Bones / Q000378:metabolism; D050658:Core Binding Factor beta Subunit; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000378:metabolism; D008969:Molecular Sequence Data; D015530:Nuclear Matrix / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
C493692:CBFB protein, human; D050658:Core Binding Factor beta Subunit; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D050656:Transcription Factor AP-2; D014157:Transcription Factors