Induction of cyclin D1 by simian virus 40 small tumor antigen.
Cell-cycle progression is mediated by a co-ordinated interaction between cyclin-dependent kinases and their target proteins including the pRB and E2F/DP-1 complexes. Immunoneutralization and antisense experiments have established that the abundance of cyclin D1, a regulatory subunit of the cyclin-dependent kinases, may be rate-limiting for G1 phase progression of the cell cycle. Simian virus 40 (SV40) small tumor (t) antigen is capable of promoting G1 phase progression and augments substantially the efficiency of SV40 transformation through several distinct domains. In these studies, small t antigen stimulated cyclin D1 promoter activity 7-fold, primarily through an AP-1 binding site at -954 with additional contributions from a CRE site at -57. The cyclin D1 AP-1 and CRE sites were sufficient for activation by small t antigen when linked to an heterologous promoter. Point mutations of small t antigen between residues 97-103 that reduced PP2A binding were partially defective in the induction of the cyclin D1 promoter. These mutations also reduced activation of MEK1 and two distinct members of the mitogen-activated protein kinase family, the ERKs (extracellular signal regulated kinases) and the SAPKs (stress-activated protein kinases), in transfected cells. Dominant negative mutants of either MEK1, ERK or SEK1, reduced small t-dependent induction of the cyclin D1 promoter. SV40 small t induction of the cyclin D1 promoter involves both the ERK and SAPK pathways that together may contribute to the proliferative and transformation enhancing activity of small t antigen.
Department of Medicine, Lurie Cancer Center, Northwestern University, Chicago, IL 60611, USA.
G
G
Watanabe
A
A
Howe
R J
RJ
Lee
C
C
Albanese
I W
IW
Shu
A N
AN
Karnezis
L
L
Zon
J
J
Kyriakis
K
K
Rundell
R G
RG
Pestell
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D002472:Cell Transformation, Viral; D002522:Chlorocebus aethiops; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000096:biosynthesis*; D016193:G1 Phase; D017930:Genes, Reporter; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000096:biosynthesis; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D013539:Simian virus 40 / Q000502:physiology*; D014162:Transfection
D000957:Antigens, Viral, Tumor; D016213:Cyclins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D011994:Recombinant Proteins; D019938:Cyclin D1; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human