Characterization of a 300 kbp Region of Human DNA Containing the Type II Hair Keratin Gene Domain

An aberrant truncated hHb1 hair keratin transcript, named hHb1-⌬N, was previously identified in breast carcinomas. No normal tissue tested so far, including hairy skin, expressed hHb1-⌬N, indicating that hHb1-⌬N is related to carcinogenesis. In the present study, we investigated the mechanism by which such truncated transcript was generated in breast cancer cell lines. We found that hHb1-⌬N transcription is initiated at an unusual cryptic promoter within the fourth intron of the hHb1 gene and is dependent on two proximal Sp1 binding sites for its baseline activity. Moreover, hHb1-⌬N transcription is increased in response to DNA demethylation by the 5-aza-2-deoxycytidine drug. This induction is dependent on protein neosynthesis, indicating that an additional factor is required. In addition, we showed that the hHb1-⌬N transcript is translated in vivo as a truncated hHb1 protein that is missing the 270 amino-terminal residues. The hHb1-⌬N protein exhibits a filament pattern throughout the cytoplasm and partially co-localizes with cytokeratin filaments, indicating its participation in the cytoskeleton network. hHb1-⌬N might alter the adhesive properties of cancer cells.

“…5, A and C). In addition, six basic hair keratin genes have been identified (3). hHb1 hair keratin is highly related to hHb6 (GenBank accession number AJ000263) (23).…”

Section: D)mentioning

confidence: 99%

Transcription Regulation and Protein Subcellular Localization of the Truncated Basic Hair Keratin hHb1-ΔN in Human Breast Cancer Cells

Boulay¹,

Régnier

Anglard

et al. 2001

“…In the past years, our laboratory has elucidated the organization of the human type I and type II hair keratin gene loci and characterized the sequential expression of their members during trichocyte differentiation (12)(13)(14)(15) Based on this knowledge, we selected three human type I hair keratin genes hHa5, hHa2, and hHa7 as well as the transcribed pseudogene hHaA, whose mRNA expression patterns in the lower hair forming compartment of the human hair follicle (13,16) corresponded to that described for Hoxc13 in mouse hair follicles (6), and investigated whether they are target genes for HOXC13. In the present study, we provide strong evidence that these hair keratin genes are transcriptionally up-regulated by HOXC13 primarily via binding of the transcription factor to distinct core recognition motifs, TAAT and TTAT, in the respective proximal promoters.…”

mentioning

confidence: 99%

HOXC13 Is Involved in the Regulation of Human Hair Keratin Gene Expression

Jave-Suárez¹,

Winter²,

Langbein³

et al. 2002

Self Cite

124

108

At present, HOXC13 is the only member of the HOX multigene family that produces a fragile hair phenotype when mutated or overexpressed in mice. To determine whether hair keratin genes are targets for this transcription factor, we analyzed the HOXC13 responsiveness of human hair keratin genes, whose expression matched that of nuclear HOXC13, immunologically revealed in cells of the lower hair-forming compartment of the human anagen hair follicle. We show that HOXC13, but not a homeobox-deleted HOXC13, strongly activated the promoters of the genes, with the respective proximal promoter regions being sufficient for optimal activation. The hair keratin promoters contained numerous putative Hox binding core motifs TAAT, TTAT, and TTAC. Electrophoretic mobility shift assays revealed that HOXC13 bound exclusively to distinct TAAT and TTAT core motifs that were clearly concentrated in the proximal promoter regions. A comparison of the sequences flanking HOXC13 binding and nonbinding core motifs, respectively, allowed the deduction of an extended 8-bp HOXC13 consensus binding sequence TT(A/T)ATNPuPu. Thus, the DNA binding conditions for HOXC13 were distinct from those of other members of the paralogous group 13, i.e. murine Hoxb13 and HOXd13, for which previous investigations yielded the consensus binding sequence TTTA(T/C)NPuPu. Collectively, our data speak for a direct involvement of HOXC13 in the control of hair keratin expression during early trichocyte differentiation.

“…The main structural proteins of the hair fiber are the hair keratins and the hair keratin-associated proteins, KAPs, 1 the latter being encoded by a large number of multigene families (2). Hair keratins, a subset of the large keratin family whose members are found in all cells of epithelial origin (3,4), represent two multigene families, the type I (acidic) and type II (basic) families that comprise 15 members in humans (5,6). They form the 8 -10-nm intermediate filaments of trichocytes by co-polymerization of type I and type II members, which are differentially expressed during hair fiber development (7,8).…”

mentioning

confidence: 99%

Characterization of a First Domain of Human High Glycine-Tyrosine and High Sulfur Keratin-associated Protein (KAP) Genes on Chromosome 21q22.1

Rogers¹,

Langbein²,

Winter³

et al. 2002

Self Cite

105

106

Analysis of the EBI/GeneBankTM data base using nonhuman hair keratin-associated protein (KAP) cDNA sequences as a query resulted in the identification of a first domain of high glycine-tyrosine and high sulfur KAP genes located on human chromosome 21q22.1. This domain, present on the DNA accession numbers AP001078 and AP001709, was ϳ535 kb in size and contained 17 high glycine-tyrosine and 7 high sulfur KAP genes, as well as 9 KAP pseudogenes. Based on amino acid sequence comparisons of the encoded proteins, the KAP genes could be divided into seven high glycinetyrosine gene families (KAP6 -KAP8, and KAP19 -KAP22) and four high sulfur gene families (KAP11, KAP13, KAP15, and KAP23). The high glycine-tyrosine genes described here appear to represent the complete set of this type of KAP genes present in the human genome. Both systematic cDNA isolation studies from an arrayed scalp cDNA library and in situ hybridization expression studies of all of the KAP genes identified in the 21q22.1 region revealed varying degrees and regions of expression of 11 members of the high tyrosine-glycine genes and 6 members of the high sulfur KAP genes in the hair forming compartment.