CLED: a calcium-linked protein associated with early epithelial differentiation

Exp Cell Res. 2000 Aug 25;259(1):96-106. doi: 10.1006/excr.2000.4922.


Although it has been well established that Ca(2+) plays a key role in triggering keratinocyte differentiation, relatively little is known about the molecules that mediate this signaling process. By analyzing a bovine corneal epithelial subtraction cDNA library, we have identified a novel gene that we named CLED (calcium-linked epithelial differentiation), which encodes a messenger RNA present in all stratified squamous epithelia, hair follicle, the bladder transitional epithelium, and small intestinal epithelium. The deduced amino acid sequence of CLED, based on a bovine partial cDNA and its full-length, human and mouse homologues that have been described only as ESTs, contains 2 EF-hand Ca(2+)-binding domains, a myristoylation motif, and several potential protein kinase phosphorylation sites; the CLED protein is therefore related to the S100 protein family. In all stratified squamous epithelia, the CLED message is associated with the intermediate cell layers. Similar CLED association with cells that are above the proliferative compartment but below the terminally differentiated compartment is seen in hair follicle, bladder, and small intestinal epithelia. The only exception is corneal epithelium, where CLED is expressed in both basal and intermediate cells. The presence of CLED in corneal epithelial basal cells, but not in the adjacent limbal basal (stem) cells, provides additional, strong evidence for the unique lateral heterogeneity of the limbal/corneal epithelium. These results suggest that CLED, via Ca(2+)-related mechanisms, may play a role in the epithelial cell's commitment to undergo early differentiation, and that its down-regulation is required before the cells can undergo the final stages of terminal differentiation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Calcium / metabolism*
  • Calcium Signaling / physiology
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / metabolism*
  • Cattle
  • Cell Differentiation / physiology
  • Epidermal Cells
  • Epidermis / metabolism
  • Epithelium, Corneal / cytology
  • Epithelium, Corneal / metabolism
  • Gastric Mucosa / cytology
  • Gene Expression / physiology
  • Gene Library
  • Hair Follicle / cytology
  • Hair Follicle / metabolism
  • Humans
  • Keratinocytes / cytology*
  • Keratinocytes / metabolism*
  • Mice
  • Molecular Sequence Data
  • S100 Proteins / genetics
  • Sequence Homology, Amino Acid
  • Urinary Bladder / cytology


  • CLED protein, Bos taurus
  • Calcium-Binding Proteins
  • S100 Proteins
  • Calcium