CHAPTER 19
A Structural Model for the PS3 Complex with DNA
Response Elements: Implications for PS3 Function
and Future Research Directions
R. E. HARRINGTON!, V. B. ZHURKIN 2 and S. R. DURELL 2 , R. L. Jernigan 2 ,
A. K. NAGAICH 1 ,3 and E. ApPELLA 3
1
Introduction
Wild type p53 is a nuclear phosphoprotein that occurs in a wide variety of organisms and plays a central role in the regulation of cellular growth and in tumor
suppression. It was first described as a cellular protein that co-precipitated with
the large T antigen of SV40 (Lane and Crawford, 1979; Linzer and Levine, 1979)
whose synthesis was enhanced in chemically induced tumors (DeLeo et ai., 1979).
It is a potent, pleiotropic transcription factor that is activated in response to a
variety of DNA damaging agents. Such activation can lead to cell cycle arrest at
the G lIS phase checkpoint (Kuerbitz et ai., 1992; Hartwell and Kastan, 1994) or to
induction of apoptosis (Lin et ai., 1992; Lowe et al., 1993). It has long been known
that p53 inactivation by mutation or deletion (along with loss of the wild type
allele) or by interaction with cellular or viral proteins is highly correlated with a
wide variety of human cancers (Hollstein et ai., 1991; Levine et ai., 1991; Lane,
1992; Vogelstein and Kinzler, 1992; Meltzer, 1994) through the development of
dominant negative tum orogenic phenotypes (Harris, 1993; Levine, 1993, 1997).
Virtually all of the presently known biological functions of p53 depend critically upon its DNA binding properties. Studies of tum orogenic p53 mutants have
shown that most of these are defective in DNA binding and consequently cannot
activate transcription (Pavletich et ai., 1993; Arrowsmith and Morin, 1996; Jayaraman et ai., 1997). Additional evidence is based upon the role of p53 as a transcription factor or transcriptional enhancer for genes that mediate DNA damage
repair and growth arrest through their gene products (EI-Deiry et al., 1993; Milner, 1994; Prives, 1994). The latter include Gadd45, which is implicated in the
stimulation of DNA repair (Marx, 1994; Smith et al., 1994) and Wa!lICipllSdil
which codes for p21, a protein that inhibits several cyclin-dependent protein
kinases necessary for cell cycle progression from G 1 into S phase (Hartwell and
Kastan, 1994; Pines, 1994). p53 can also induce apoptosis by responding to the
induction of oncogenes such as c-Myc (Hermeking and Eick, 1994; Symonds et
ai., 1994; Wu and Levine, 1994). Thus, it is becoming clear that sequence specific
DNA binding and transactivation are the key activities that control most of the
biological functions of p53 (Prives et al., 1994; Jayaraman et ai., 1997).
1 Department of Microbiology, Arizona State University, Tempe, AZ 85287 - 270 1.
2 Laboratory of Experimental and Computational Biology.
3 Laboratory of Cell Biology, NCI, National Institutes of Health, Bethesda, MD 20892 USA.
A Structural Model for the PS3 Complex with DNA
Response Elements: Implications for PS3 Function
and Future Research Directions
R. E. HARRINGTON!, V. B. ZHURKIN 2 and S. R. DURELL 2 , R. L. Jernigan 2 ,
A. K. NAGAICH 1 ,3 and E. ApPELLA 3
1
Introduction
Wild type p53 is a nuclear phosphoprotein that occurs in a wide variety of organisms and plays a central role in the regulation of cellular growth and in tumor
suppression. It was first described as a cellular protein that co-precipitated with
the large T antigen of SV40 (Lane and Crawford, 1979; Linzer and Levine, 1979)
whose synthesis was enhanced in chemically induced tumors (DeLeo et ai., 1979).
It is a potent, pleiotropic transcription factor that is activated in response to a
variety of DNA damaging agents. Such activation can lead to cell cycle arrest at
the G lIS phase checkpoint (Kuerbitz et ai., 1992; Hartwell and Kastan, 1994) or to
induction of apoptosis (Lin et ai., 1992; Lowe et al., 1993). It has long been known
that p53 inactivation by mutation or deletion (along with loss of the wild type
allele) or by interaction with cellular or viral proteins is highly correlated with a
wide variety of human cancers (Hollstein et ai., 1991; Levine et ai., 1991; Lane,
1992; Vogelstein and Kinzler, 1992; Meltzer, 1994) through the development of
dominant negative tum orogenic phenotypes (Harris, 1993; Levine, 1993, 1997).
Virtually all of the presently known biological functions of p53 depend critically upon its DNA binding properties. Studies of tum orogenic p53 mutants have
shown that most of these are defective in DNA binding and consequently cannot
activate transcription (Pavletich et ai., 1993; Arrowsmith and Morin, 1996; Jayaraman et ai., 1997). Additional evidence is based upon the role of p53 as a transcription factor or transcriptional enhancer for genes that mediate DNA damage
repair and growth arrest through their gene products (EI-Deiry et al., 1993; Milner, 1994; Prives, 1994). The latter include Gadd45, which is implicated in the
stimulation of DNA repair (Marx, 1994; Smith et al., 1994) and Wa!lICipllSdil
which codes for p21, a protein that inhibits several cyclin-dependent protein
kinases necessary for cell cycle progression from G 1 into S phase (Hartwell and
Kastan, 1994; Pines, 1994). p53 can also induce apoptosis by responding to the
induction of oncogenes such as c-Myc (Hermeking and Eick, 1994; Symonds et
ai., 1994; Wu and Levine, 1994). Thus, it is becoming clear that sequence specific
DNA binding and transactivation are the key activities that control most of the
biological functions of p53 (Prives et al., 1994; Jayaraman et ai., 1997).
1 Department of Microbiology, Arizona State University, Tempe, AZ 85287 - 270 1.
2 Laboratory of Experimental and Computational Biology.
3 Laboratory of Cell Biology, NCI, National Institutes of Health, Bethesda, MD 20892 USA.