Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function.
The D-type cyclin-dependent kinases CDK4 and CDK6 are complexed with many small cellular proteins (p14, p15, p16, p18, and p20). We have isolated cDNA sequences corresponding to the MTS2 genomic fragment that encodes the CDK4- and CDK6-associated p14 protein. By use of a yeast interaction screen to search for CDK6-interacting proteins, we have also identified an 18-kD human protein, p18, that is a homolog of the cyclin D-CDK4 inhibitors p16 (INK4A/MTS1) and p14 (MTS2/INK4B). Both in vivo and in vitro, p18 interacts strongly with CDK6, weakly with CDK4, and exhibits no detectable interaction with the other known CDKs. Recombinant p18 inhibits the kinase activity of cyclin D-CDK6. Distinct from the p21/p27 family of CDK inhibitors that form ternary complexes with cyclin-CDKs, only binary complexes of p14, p16, and p18 were found in association with CDK4 and/or CDK6. Ectopic expression of p18 or p16 suppresses cell growth with a correlated dependence on endogenous wild-type pRb.
Guan
K L
KL
Department of Biological Chemistry, University of Michigan, Ann Arbor 48109-0606.
Jenkins
C W
CW
Li
Y
Y
Nichols
M A
MA
Wu
X
X
O'Keefe
C L
CL
Matera
A G
AG
Xiong
Y
Y
D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002455:Cell Division; D002460:Cell Line; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D003001:Cloning, Molecular; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D050763:Cyclin-Dependent Kinase Inhibitor p18; D018844:Cyclin-Dependent Kinases; D017931:DNA Primers; D004791:Enzyme Inhibitors; D005260:Female; D005656:Fungal Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins; D033921:Vesicular Transport Proteins
C493971:CDKN2C protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D017931:DNA Primers; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; C077734:NPL3 protein, S cerevisiae; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D016160:Retinoblastoma Protein; D029701:Saccharomyces cerevisiae Proteins; D025521:Tumor Suppressor Proteins; C083878:VPS41 protein, S cerevisiae; D033921:Vesicular Transport Proteins; D017346:Protein Serine-Threonine Kinases; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases