p57Kip2 (cdkn1c): sequence, splice variants and unique temporal and spatial expression pattern in the rat pancreas

Abstract

The cyclin-dependent kinase (CDK) inhibitor p57Kip2 (CDKN1C) is a negative regulator of cell proliferation, binding to a variety of cyclin-CDK complexes and inhibiting their kinase activities in vitro. The p57Kip2 gene is imprinted and the maternal allele is expressed in terminally differentiated cells, including human b-cells. Somatic loss of p57Kip2 expression is associated with increased b-cell proliferation in the focal form of Hyperinsulinism of Infancy. We cloned and sequenced the rat ortholog of p57 Kip2 , and demonstrate that it is highly homologous to the mouse gene. However, the human and rodent genes are quite divergent. Despite having highly homologous C-and N-terminal domains, the mid-portion of the human gene is entirely different from that of its rodent counterparts. Expression of p57Kip2 was evaluated during fetal and postnatal development, and a highly cell-specific, temporal and spatial expression profile was found. In contrast to other tissues, the expression pattern in rat pancreas was entirely opposite from that previously reported in man, with high levels of expression in rodent exocrine cells, but no expression in b-cells during any stage of development. These findings demonstrate that p57Kip2 expression is highly regulated. In the pancreas, the functional significance of this gene appears to be quite different in humans when compared with rodents, suggesting that a better understanding of the function of this protein may provide new insights into the mechanisms involved in the control of human b-cell mass.

p57KIP2: “Kip”ing the Cell under Control

“…Most of the data have been obtained from rodents (14,(38)(39)(40)(41)(42)(43)(44) and only sporadically in humans (11,12,44,45). Specifically, the highest levels and most widespread tissue localization were observed during organogenesis.…”

“…KIP2 is present in all major organs during embryonic development, and its levels of expression peaks at key stages of differentiation for each specific organ (14,39,41). Afterward, its expression declines to low or undetectable levels in several tissues (14,39,41), and only organs that mature after birth, such as testis (44), exhibit strong p57 KIP2 staining in certain tissue compartments.…”

“…The major transcript corresponds to the one with the whole intron 1 spliced out (15). The splicing and expression pattern is conserved among humans and rodents (14). containing a conserved motif, named QT box (Fig.…”

“…12). Mouse and rat p57 KIP2 reside in the distal region of chromosomes 7 and 1, respectively (13,14). The coding region of CDKN1C consists of four exons separated by three introns ( Fig.…”

Wnt7b and Its Direct Target p57kip2 in Renal Medulla Development

“…214 This variant splicing is conserved from rodents to humans and produces heterogeneity in the amino terminus of p57kip2 protein. 214,218 Downstream of the amino terminus, murine p57kip2 has 4 domains; (I) a cyclin dependent kinase (CDK) inhibitory domain similar to p21 and p27, (II) a proline rich domain containing a MAP kinase phosphorylation site, (III) an acidic domain containing tandem repeats of a 4 amino acid sequence, and (IV) a c-terminal domain similar to p27 containing a CDK phosphorylation site and a nuclear localization signal. 214,216 In humans, domains I and IV are conserved, but domains II and III are replaced with a single domain of proline-alanine repeats (PAPA domain).…”