Use of a cryptic splice site for the expression of huntingtin interacting protein 1 in select normal and neoplastic tissues

Chiron W. Graves, Steven T. Philips, Sarah V. Bradley, Katherine I. Oravecz-Wilson, Lina Li, Alice Gauvin, Theodora S. Ross

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Huntingtin interacting protein 1 (HIP1) is a 116-kDa endocytic protein, which is necessary for the maintenance of several tissues in vivo as its deficiency leads to degenerative adult phenotypes. HIP1 deficiency also inhibits prostate tumor progression in mice. To better understand how deficiency of HIP1 leads to such phenotypes, we analyzed tumorigenic potential in mice homozygous for a Hip1 mutant allele, designated Hip1Δ3-5, which is predicted to result in a frameshifted, nonsense mutation in the NH2 terminus of HIP1. In contrast to our previous studies using the Hip1 null allele, an inhibition of tumorigenesis was not observed as a result of the homozygosity of the nonsense Δ3-5 allele. To further examine the contrasting results from the prior Hip1 mutant mice, we cultured tumor cells from homozygous Δ3-5 allele-bearing mice and discovered the presence of a 110-kDa form of HIP1 in tumor cells. Upon sequencing of Hip1 DNA and message from these tumors, we determined that this 110-kDa form of HIP1 is the product of splicing of a cryptic U12-type AT-AC intron. This event results in the insertion of an AG dinucleotide between exons 2 and 6 and restoration of the reading frame. Remarkably, this mutant protein retains its capacity to bind lipids, clathrin, AP2, and epidermal growth factor receptor providing a possible explanation for why tumorigenesis was not altered after this knockout mutation. Our data show how knowledge of the transcript that is produced by a knockout allele can lead to discovery of novel types of molecular compensation at the level of splicing.

Original languageEnglish (US)
Pages (from-to)1064-1073
Number of pages10
JournalCancer Research
Volume68
Issue number4
DOIs
StatePublished - Feb 15 2008

Fingerprint

RNA Splice Sites
Alleles
Carcinogenesis
Cultured Tumor Cells
Phenotype
Protein Deficiency
Reading Frames
Neoplasms
Clathrin
Nonsense Codon
Mutant Proteins
DNA Sequence Analysis
Epidermal Growth Factor Receptor
Introns
Huntingtin Protein
Prostate
Exons
Maintenance
Lipids
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Use of a cryptic splice site for the expression of huntingtin interacting protein 1 in select normal and neoplastic tissues. / Graves, Chiron W.; Philips, Steven T.; Bradley, Sarah V.; Oravecz-Wilson, Katherine I.; Li, Lina; Gauvin, Alice; Ross, Theodora S.

In: Cancer Research, Vol. 68, No. 4, 15.02.2008, p. 1064-1073.

Research output: Contribution to journalArticle

Graves, Chiron W. ; Philips, Steven T. ; Bradley, Sarah V. ; Oravecz-Wilson, Katherine I. ; Li, Lina ; Gauvin, Alice ; Ross, Theodora S. / Use of a cryptic splice site for the expression of huntingtin interacting protein 1 in select normal and neoplastic tissues. In: Cancer Research. 2008 ; Vol. 68, No. 4. pp. 1064-1073.
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