Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF

Dawn E Quelle; Mangeng Cheng; Richard A Ashmun; Charles J Sherr

doi:10.1073/pnas.94.2.669

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Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF

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Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF

Dawn E Quelle, Mangeng Cheng, Richard A Ashmun and Charles J Sherr

Proceedings of the National Academy of Sciences - PNAS, Vol.94(2), pp.669-673

01/21/1997

DOI: 10.1073/pnas.94.2.669

PMID: 9012842

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Abstract

The INK4a gene, one of the most frequently disrupted tumor suppressor loci in human cancer, encodes two unrelated proteins, p16INK4a and p19ARF, each of which is capable of inducing cell cycle arrest. Splicing of alternative first exons (1α vs. 1β) to a common second exon within INK4a generates mRNAs in which exon 2 sequences are translated in two different reading frames. One of the products, the cyclin D-dependent kinase inhibitor p16INK4a, is functionally inactivated by mutations or deletions in a wide variety of cancers. However, because many such mutations reside in exon 2, they also affect the alternative reading frame (ARF) protein. To determine whether such mutations disrupt p19ARF function, we introduced naturally occurring missense mutations into mouse INK4a exon 2 sequences and tested mutant p16INK4a and p19ARF proteins for their ability to inhibit cell cycle progression. Six p19ARF point mutants remained fully active in mediating cell cycle arrest in NIH 3T3 fibroblasts, whereas two of the corresponding mutations within p16INK4a resulted in complete loss of activity. Analysis of p19ARF deletion mutants indicated that the unique aminoterminal domain encoded by exon 1β was both necessary and sufficient for inducing G1 arrest. Therefore, cancer-associated mutations within exon 2 of the INK4a gene specifically target p16INK4a, and not p19ARF, for inactivation.

Biological Sciences

cyclin D-dependent kinases

INK4a tumor suppressor

Details

Title: Subtitle: Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF
Creators: Dawn E Quelle - Howard Hughes Medical Institute and Departments of
Mangeng Cheng - Howard Hughes Medical Institute and Departments of
Richard A Ashmun - Howard Hughes Medical Institute and Departments of
Charles J Sherr - Howard Hughes Medical Institute and Departments of
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.94(2), pp.669-673
DOI: 10.1073/pnas.94.2.669
PMID: 9012842
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 01/21/1997
Academic Unit: Pathology; Neuroscience and Pharmacology
Record Identifier: 9984040578302771

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