Misexpression of disrupted HMGI architectural factors activates alternative pathways of tumorigenesis.
Cancer arises from aberrations in the genetic mechanisms that control growth and differentiation. HMGI-C and HMGI(Y) are members of the HMGI family of architectural factors expressed in embryonic or undifferentiated cells and highly associated with transformation. Translocations of 12q13-15 in lipomas (fat cell tumors) disrupt HMGI-C and fuse its DNA-binding domains to novel transcriptional regulatory domains. This study shows that in a rare, karyotypically distinct group of human lipomas, rearrangements of 6p21-23 produce internal deletions within HMGI(Y). Activation of the rearranged alleles leads to expression of aberrant HMGI(Y) transcripts in differentiated adipocytes. A molecular analysis of these transcripts demonstrates that fusion of HMGI DNA-binding domains to putative transcriptional regulatory domains was not necessary for lipoma formation. However, such fusions may facilitate tumor development because activation of the wild-type HMGI allele, normally required for tumorigenesis, is bypassed in lipomas which express chimeric HMGI proteins. We hypothesize that HMGI misexpression in a differentiated cell is a pivotal event in benign tumorigenesis, and the molecular pathway of tumor development depends upon the precise nature of HMGI disruption.
Tkachenko
A
A
Department of Biochemistry, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635, USA.
Ashar
H R
HR
Meloni
A M
AM
Sandberg
A A
AA
Chada
K K
KK
D000483:Alleles; D002454:Cell Differentiation / Q000235:genetics; D002896:Chromosomes, Human, Pair 6; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D025741:HMGA1a Protein; D006609:High Mobility Group Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007621:Karyotyping; D008067:Lipoma / Q000235:genetics* / Q000378:metabolism*; D016296:Mutagenesis; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017384:Sequence Deletion; D014158:Transcription, Genetic
D006609:High Mobility Group Proteins; D011993:Recombinant Fusion Proteins; D025741:HMGA1a Protein