PMID- 10491434
OWN - NLM
STAT- MEDLINE
DCOM- 19991007
LR  - 20190513
IS  - 0027-8874 (Print)
IS  - 0027-8874 (Linking)
VI  - 91
IP  - 18
DP  - 1999 Sep 15
TI  - Biologic and biochemical analyses of p16(INK4a) mutations from primary tumors.
PG  - 1569-74
AB  - BACKGROUND: Point mutations in the tumor suppressor gene p16(INK4a) (also known
      as p16, CDKN2, MTS1, and INK4a) are found in many tumor types. Because the
      function of the products of these naturally occurring mutants has not been fully 
      explored, we investigated the functional activities of a wide range of naturally 
      occurring p16 mutant proteins. METHODS: Sixteen cancer-associated p16 mutant
      proteins, resulting from missense mutations, were characterized for their ability
      to bind and inhibit the cyclin-dependent kinases (CDK4 and CDK6) and to induce
      cell cycle arrest in G(1) phase. RESULTS/CONCLUSIONS: Among 16 mutants analyzed, 
      nine had detectable functional defects. Three mutants (D84V, D84G, and R87P) had 
      defects in CDK binding, kinase inhibition, and cell cycle arrest. The
      corresponding mutations are located in the third ankyrin repeat in a highly
      conserved region believed to form the CDK binding cleft. Three mutants (P48L,
      D74N, and R87L) had defects in kinase inhibition and cell cycle arrest. Among the
      10 mutants with normal CDK binding and inhibitory activity, three mutants (N71S, 
      R80L, and H83Y) had defects only in their ability to induce cell cycle arrest.
      Thus, p16 mutant proteins that retain CDK4 and CDK6 binding may have more subtle 
      functional defects. All nine mutations leading to functional impairments mapped
      to the central portion of the p16 protein. Ankyrin repeats II and III appear more
      critical to p16 function, and mutations in ankyrin repeats I and IV are less
      likely to disrupt p16 function.
FAU - Yarbrough, W G
AU  - Yarbrough WG
AD  - Department of Surgery, Division of Otolaryngology/Lineberger Comprehensive Cancer
      Center, Chapel Hill, NC 27599-7295, USA. wgy@med.unc.edu
FAU - Buckmire, R A
AU  - Buckmire RA
FAU - Bessho, M
AU  - Bessho M
FAU - Liu, E T
AU  - Liu ET
LA  - eng
GR  - K08CA72968/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Natl Cancer Inst
JT  - Journal of the National Cancer Institute
JID - 7503089
RN  - 0 (Ankyrins)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 2.5.1.18 (Glutathione Transferase)
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 (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
CIN - J Natl Cancer Inst. 2000 May 3;92(9):758-60. PMID: 10793118
MH  - Amino Acid Sequence
MH  - Ankyrins/*genetics
MH  - Cyclin-Dependent Kinase 4
MH  - Cyclin-Dependent Kinase 6
MH  - Cyclin-Dependent Kinase Inhibitor p16/chemistry/*genetics/metabolism
MH  - Cyclin-Dependent Kinases/antagonists & inhibitors/*metabolism
MH  - G1 Phase/*genetics
MH  - Genes, p16
MH  - Glutathione Transferase/genetics
MH  - Humans
MH  - Molecular Sequence Data
MH  - *Mutation, Missense
MH  - Protein Binding
MH  - Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - *Proto-Oncogene Proteins
EDAT- 1999/09/24 00:00
MHDA- 1999/09/24 00:01
CRDT- 1999/09/24 00:00
PHST- 1999/09/24 00:00 [pubmed]
PHST- 1999/09/24 00:01 [medline]
PHST- 1999/09/24 00:00 [entrez]
AID - 10.1093/jnci/91.18.1569 [doi]
PST - ppublish
SO  - J Natl Cancer Inst. 1999 Sep 15;91(18):1569-74. doi: 10.1093/jnci/91.18.1569.