Cloning and characterization of murine p16INK4a and p15INK4b genes.
Progression through the G1 phase of the cell cycle is regulated in part by the D-type cyclin-dependent kinases, cdk4 and cdk6. Genes encoding two specific inhibitors of these kinases, human p16(INK4a/MTS1) and p15(INK4b/MTS2), map to a region of common cytogenetic abnormalities on chromosome 9p21. The murine cognates of these genes were isolated and identified as mouse p16INK4a and p15INK4b based on their homology to their human counterparts and their selective transcriptional induction by SV40T-antigen and TGF-beta, respectively. Both genes map to position C3-C6 on mouse chromosome 4, in a region syntenic with human chromosome 9p. Amplification of polyadenylated mRNA by polymerase chain reactions revealed no expression of mouse p16INK4a in many normal tissues, whereas p15INK4b was expressed ubiquitously. Like human p16INK4a, mouse p16INK4a binds specifically to cdk4 and cdk6 in vitro and inhibits the phosphorylation of the retinoblastoma protein, pRb, by each of these cyclin D-dependent kinases. In mouse MEL erythroleukemia cells, p16INK4a associates preferentially with cdk6 under conditions where cdk4 and cdk6 are coexpressed at equivalent levels. Expression vectors encoding human or mouse p16INK4a caused G1 phase arrest in NIH3T3 fibroblasts, and cyclin D1- and cdk4-dependent pRb kinase activities were inhibited in the p16INK4a-arrested cells.
Quelle
D E
DE
Howard Hughes Medical Institute, Memphis, Tennessee, USA.
Ashmun
R A
RA
Hannon
G J
GJ
Rehberger
P A
PA
Trono
D
D
Richter
K H
KH
Walker
C
C
Beach
D
D
Sherr
C J
CJ
Serrano
M
M
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002869:Chromosome Aberrations; D025063:Chromosome Disorders; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D003001:Cloning, Molecular; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D016193:G1 Phase; D015870:Gene Expression; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice / Q000235:genetics*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D002352:Carrier Proteins; C493968:Cdkn2b protein, mouse; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins