p57(KIP2) expression in normal islet cells and in hyperinsulinism of infancy.
Most cases of hyperinsulinism of infancy (HI) are caused by mutations in either the sulfonylurea receptor-1 (SUR1) or the inward rectifying K(+) channel Kir6.2, two subunits of the beta-cell ATP-sensitive K(+) channel (K(ATP) channel). Histologically, HI can be divided into two major subtypes. The diffuse form is recessively inherited and involves all beta-cells within the pancreas. Focal HI consists of adenomatous hyperplasia within a limited region of the pancreas, and it is caused by somatic loss of heterozygosity (LOH), including maternal Ch11p15-ter in a beta-cell precursor carrying a germ-line mutation in the paternal allele of SUR1 or Kir6.2. Several imprinted genes are located within this chromosomal region, some of which, including p57(KIP2) and IGF-II, have been associated with the regulation of cell proliferation. Using double immunostaining, we examined p57(KIP2) expression in different islet cell types, in control pancreases from different developmental stages (n = 15), and in pancreases from patients with both diffuse (n = 4) and focal HI (n = 9). Using immunofluorescence and computerized image analysis, we quantified IGF-II expression in beta-cells from patients with focal HI (n = 8). Within the pancreas, p57(KIP2) was specifically localized to the endocrine portion. beta-Cells demonstrated the highest frequency of expression (34.9 +/- 2.7%) compared with approximately 1-3% in other cell types. The fraction of beta-cells expressing p57(KIP2) did not vary significantly during development. beta-Cells within the focal lesions did not express p57(KIP2), whereas IGF-II staining inside focal lesions was mildly increased compared with unaffected surrounding tissue. In conclusion, we demonstrate that p57(KIP2) is expressed and is paternally imprinted in human pancreatic beta-cells. Loss of expression in focal HI is caused by LOH and is associated with increased proliferation and increased IGF-II expression. Manipulation of p57(KIP2) expression in beta-cells may provide a mechanism by which proliferation can be modulated, and thus this gene is a potential therapeutic target for reversing the beta-cell failure observed in diabetes.
Kassem
S A
SA
Department of Endocrinology and Metabolism, Hebrew University, Hadassah Medical Center, Jerusalem, Israel.
Ariel
I
I
Thornton
P S
PS
Hussain
K
K
Smith
V
V
Lindley
K J
KJ
Aynsley-Green
A
A
Glaser
B
B
D002467:Cell Nucleus / Q000737:chemistry; D050761:Cyclin-Dependent Kinase Inhibitor p57; D003593:Cytoplasm / Q000737:chemistry; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics* / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D007223:Infant; D007231:Infant, Newborn; D007335:Insulin-Like Growth Factor II / Q000032:analysis / Q000235:genetics; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*
C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D009687:Nuclear Proteins; D007335:Insulin-Like Growth Factor II