Cancer-associated mis-sense and deletion mutations impair p16INK4 CDK inhibitory activity

International Journal of Cancer. Journal International Du Cancer
R LilischkisR L Sutherland

Abstract

The p16INK4 gene is a candidate tumour-suppressor gene which maps to the genomic locus 9p21, and mutations of this gene are associated with melanoma and other cancers. Biochemical studies suggest that p16INK4 mediates its effects by specifically inhibiting the G1 cyclin-dependent kinases CDK4 and CDK6, thereby regulating the progression through G1 into S phase of the cell cycle. To evaluate the functional effects of mutations in p16INK4 which have been observed in primary cancers and cancer cell lines, we constructed a series of deletion mutants comprising amino acid regions 9-72, 9-131, 73-131 and 73-156; a mis-sense mutation identified in melanoma (Arg87Pro); and the polymorphism Ala48Thr and investigated their ability to inhibit cyclin D1/CDK4 kinase activity in vitro. Removal of 25 amino acids from the carboxy terminus of p16INIK4 (9-131) had little impact on its inhibitory activity. In contrast, deletion of the 65 N-terminal amino acids comprising the first and second ankyrin repeats of p16INK4 (73-131) abolished its inhibitory activity. The carboxy (73-156) and amino termial (9-72) fragments of p16INK4 also failed to inhibit cyclin D1/CDK4 activity. These results indicate that the core region (73-131) as well as amino aci...Continue Reading

References

Jul 3, 1995·Proceedings of the National Academy of Sciences of the United States of America·R H MedemaR A Weinberg
May 1, 1995·Trends in Biochemical Sciences·C J Sherr
May 1, 1995·Nature Genetics·K RanadeN C Dracopoli
Apr 1, 1995·Trends in Genetics : TIG·A Kamb
Nov 1, 1994·Molecular and Cellular Biology·M MatsuokaC J Sherr
Aug 1, 1994·Genes & Development·H ZhangD Beach
Sep 1, 1994·Nature Genetics·C J HussussianN C Dracopoli
Jun 1, 1993·Trends in Biochemical Sciences·J Pines

❮ Previous
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Citations

May 10, 2005·Journal of Medical Genetics·T DebniakJ Lubinski
Feb 14, 1998·Nature Structural Biology·N Q McDonald, G Peters
Nov 5, 1997·Human Molecular Genetics·M HarlandJ N Bishop
Jan 23, 1999·Clinical and Experimental Dermatology·J A Newton BishopD T Bishop
Mar 27, 1998·The New England Journal of Medicine·J MonzonN J Lassam
Jun 26, 2012·Biomarkers : Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals·Meenu Asaas QureshiKhurshid Iqbal Andrabi
Jun 17, 1998·The Laryngoscope·J C LangC M Weghorst
Aug 10, 2000·Neoplasia : an International Journal for Oncology Research·P PantazisJ Wyche
Dec 20, 2008·Clinics in Dermatology·Andrew A Nelson, Hensin Tsao
Apr 15, 2006·The Journal of Investigative Dermatology·Tania SpicaUNKNOWN MELAN-COHORT
Apr 23, 2008·Pathology·Nicola WayteSunil R Lakhani
Jan 24, 2007·Thoracic Surgery Clinics·Adam Yagui-BeltránDavid M Jablons
Jan 6, 2006·International Journal of Cancer. Journal International Du Cancer·Tadeusz DebniakJan Lubinski
Sep 8, 2011·Experimental Dermatology·Renato M BakosRoberto Giugliani
Jan 26, 2010·Actas dermo-sifiliográficas·S BloethnerR Kumar
Oct 31, 2002·The Journal of Investigative Dermatology·Chandra G BertramJulia A Newton Bishop
Dec 18, 1998·The Journal of Investigative Dermatology·M C FargnoliK Peris
May 13, 1999·Acta Oto-laryngologica·D G DanaheyJ C Lang
Aug 26, 1998·Biochemical and Biophysical Research Communications·H M CehaR J Slebos
Jul 2, 1999·International Journal of Cancer. Journal International Du Cancer·G J WalkerN K Hayward
Jun 20, 1997·International Journal of Cancer. Journal International Du Cancer·L TalveT Ekfors
Oct 25, 2006·Breast Cancer Research and Treatment·Tadeusz DebniakJan Lubiński
Sep 28, 1999·Oncogene·N SoufirN Basset-Seguin
Sep 18, 2007·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Ronald R de KrijgerErnst J M Speel
Aug 15, 2018·Molecular Genetics & Genomic Medicine·Baolin LiuAn-Yuan Guo
Nov 7, 2006·ORL; Journal for Oto-rhino-laryngology and Its Related Specialties·Sven KoscielnyFerdinand von Eggeling
May 14, 1998·International Journal of Cancer. Journal International Du Cancer·A RuizX Estivill
May 7, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jianping HuangPaul F Robbins
Mar 1, 2020·Cell Death & Disease·Robert H Whitaker, William J Placzek
Sep 29, 2020·Journal of Clinical and Experimental Hematopathology : JCEH·Takahisa YamashitaMichael Hummel
Aug 15, 2002·Cancer Letters·Deborah Marsh, Roberto Zori
Nov 21, 1998·Biochimica Et Biophysica Acta·M Ruas, G Peters

❮ Previous
Next ❯

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