Aberrant expression of HMGA2 in uterine leiomyoma associated with loss of TSC2 tumor suppressor gene function

Unregulated proliferation of mesenchymal cells in leiomyomas, lipomas, hamartomas,and other diseases has been linked to the high mobility group (HMGA) family of DNA architectural proteins. HMGA genes are primarily expressed during embryonal development and silenced in adult tissues but can become re...

Full description

Saved in:
Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2002-07, Vol.62 (13), p.3766-3772
Main Authors: HUNTER, Deborah S, KLOTZBÜCHER, Michael, KUGOH, Hiroyuki, CAI, Sheng-Li, MULLEN, Johanna P, MANFIOLETTI, Guidalberto, FUHRMAN, Ulrike, WALKER, Cheryl L
Format: Article
Language:English
Subjects:
Animal tumors. Experimental tumors
Animals
Biological and medical sciences
Experimental genital and mammary tumors
Female
Gene Expression Regulation, Neoplastic
Gene Silencing
Genes, Tumor Suppressor - physiology
HMGA2 Protein - biosynthesis
HMGA2 Protein - genetics
Leiomyoma - genetics
Leiomyoma - metabolism
Loss of Heterozygosity
Medical sciences
Rats
Repressor Proteins - biosynthesis
Repressor Proteins - genetics
Translocation, Genetic
Tumor Suppressor Proteins
Tumors
Up-Regulation
Uterine Neoplasms - genetics
Uterine Neoplasms - metabolism
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Unregulated proliferation of mesenchymal cells in leiomyomas, lipomas, hamartomas,and other diseases has been linked to the high mobility group (HMGA) family of DNA architectural proteins. HMGA genes are primarily expressed during embryonal development and silenced in adult tissues but can become reactivated in neoplasia as a result of chromosomal rearrangements. Although the genetic data suggesting a role for HMGA proteins in tumorigenesis are compelling, the biological role of these proteins in mesenchymal proliferation and differentiation is incompletely defined. Uterine myometria and spontaneous leiomyomas from the Eker rat, which carries a germ-line mutation in the tuberous sclerosis complex-2 (Tsc2) tumor suppressor gene, were analyzed for genetic defects in and expression of the Tsc2 and HMGA proteins. Eker leiomyomas exhibited a 50% incidence of loss of the wild-type Tsc2 allele and an almost uniform loss of protein expression, implicating loss of function of the Tsc2 gene in these tumors. Concomitantly, HMGA2 protein, which was completely absent in normal myometria, was expressed in 16 of 19 Eker leiomyomas. HMGA1 was expressed in both leiomyoma and normal myometria. No structural alterations were observed at the HMGA2 locus in either primary rat leiomyomas or leiomyoma-derived cell lines that expressed HMGA2. These data support a role for HMGA2 in the development of smooth muscle neoplasms and suggest HMGA2 expression is a point of convergence between the human disease and the Eker rat model. Furthermore, these data indicate that aberrant HMGA2 expression can result from dysfunction of the Tsc2 tumor suppressor gene, in the absence of structural alterations involving the HMGA2 locus.
ISSN:0008-5472
1538-7445