PMID- 10498896
OWN - NLM
STAT- MEDLINE
DCOM- 19991029
LR  - 20120625
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 18
IP  - 39
DP  - 1999 Sep 23
TI  - Functional evaluation of tumour-specific variants of p16INK4a/CDKN2A: correlation
      with protein structure information.
PG  - 5423-34
AB  - Inherited mutations in the CDKN2A/INK4a/MTS1 tumour suppressor gene on chromosome
      9p21 are associated with familial predisposition to melanoma and other tumour
      types. Nonsense and missense mutations are also found in a variety of sporadic
      cancers, and over 140 sequence variants have already been recorded in the
      literature. In assessing the relevance of these variants and for counselling
      members of affected families, it is important to distinguish inactivating
      mutations from harmless polymorphisms. Existing functional assays have frequently
      reached conflicting conclusions and no single test appears adequate. Here we
      evaluate a number of alternatives including a novel assay based on retroviral
      delivery of p16INK4a cDNAs into human diploid fibroblasts. Among the 17 sequence 
      variants analysed, three distinct categories can be distinguished: those that
      abrogate the binding of p16INK4a to CDK4 and CDK6, those that alter the
      properties of the protein without preventing it from interacting with CDKs, and
      those that have no discernible effect on protein function. These distinctions can
      be rationalized by considering the impact of the amino acid changes on the
      three-dimensional structure of the protein.
FAU - Ruas, M
AU  - Ruas M
AD  - Imperial Cancer Research Fund, PO Box 123, 44 Lincoln's Inn Fields, London WC2A
      3PX, UK.
FAU - Brookes, S
AU  - Brookes S
FAU - McDonald, N Q
AU  - McDonald NQ
FAU - Peters, G
AU  - Peters G
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Recombinant Proteins)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.22 (CDK4 protein, human)
RN  - EC 2.7.11.22 (CDK6 protein, human)
RN  - EC 2.7.11.22 (Cdk4 protein, mouse)
RN  - EC 2.7.11.22 (Cdk6 protein, mouse)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 6)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
SB  - IM
MH  - Alleles
MH  - Animals
MH  - Biological Assay/methods
MH  - COS Cells
MH  - Cell Division
MH  - Cells, Cultured
MH  - Cyclin-Dependent Kinase 4
MH  - Cyclin-Dependent Kinase 6
MH  - Cyclin-Dependent Kinase Inhibitor
      p16/biosynthesis/chemistry/*genetics/*physiology
MH  - Cyclin-Dependent Kinases/metabolism
MH  - Evaluation Studies as Topic
MH  - Humans
MH  - Mice
MH  - Models, Molecular
MH  - *Mutation
MH  - Neoplasms/genetics
MH  - Protein Binding
MH  - Protein Conformation
MH  - Protein-Serine-Threonine Kinases/metabolism
MH  - *Proto-Oncogene Proteins
MH  - Recombinant Proteins/genetics
MH  - Retroviridae/genetics
MH  - Structure-Activity Relationship
EDAT- 1999/09/28 00:00
MHDA- 1999/09/28 00:01
CRDT- 1999/09/28 00:00
PHST- 1999/09/28 00:00 [pubmed]
PHST- 1999/09/28 00:01 [medline]
PHST- 1999/09/28 00:00 [entrez]
AID - 10.1038/sj.onc.1202918 [doi]
PST - ppublish
SO  - Oncogene. 1999 Sep 23;18(39):5423-34. doi: 10.1038/sj.onc.1202918.