Interplay between the myc oncoprotein, cyclin-dependent kinases and e3 ubiquitin ligases

Mammalian cells grow, divide, and die in a precise and orderly fashion. For cells to grow and maintain 
their  integrity  they  need  to  communicate  at  both  intracellular  and  extracellular  level.  This 
communicative circuit is maintained by means of many different factors functioning at different level 
to  for  example  receive,  transmit  and  respond  to  the  delivered  message.  Among  these  factors  are 
transcription  factors whose  function  is  to  regulate  expression  of  genes  downstream  of  transmitted 
signals. Myc is a transcription factor that is estimated to regulate 10%A15% of the genes in the genome  
and that plays an essential role in various cellular processes required for cell growth, cell division and 
survival.    Often  communication between  the  factors  involved  in  signaling  involves  addition  of  small 
molecule moieties  such as phosphate, acetyl, ubiquitin or methyl groups  that  is exerted  through  the 
function  of  enzymes  like  kinases,  histone  acetyltransferases,  E3  ubiquitin  ligases  or  histone 
methyltransferases.  




E3 ubiquitin ligases tag their substrates by mono or polyubiquitin chain molecules that will dictate the 
fate  of  the  targeted  protein.  Ubiquitylated  proteins  are  usually  degraded  by  a  cellular  degradation 
machinery  called  the  proteasome.  However,  depending  how  ubiquitin  chain  is  formed  it  can  serve 
other roles than for protein degradation, for instance in transcription. 
The work presented in this thesis provides insights into underlying the role of a kinase, Cdk2 as well as 
two  E3  ubiquitin  ligases,  SCFFBXO28  and  VHL  in  the  regulating  the  function  of  Myc  transcription 
factor/protoAoncoprotein.  




Deregulated  function  of Myc  plays  an  important  role  in  the  development  of many  different  cancer 
types. Despite extensive studies on the function of Myc the mechanism underlying its deregulation is 
still elusive. Another oncoprotein whose deregulation is involved in development of different cancers 
is Ras. Myc and Ras are known to cooperate in cellular transformation but the mechanism underlying 
their cooperation is unclear. In paper I we provided a mechanism by which these two oncogene work 
together in tumor development. We show that Cdk2 kinase phosphorylates Myc at SerA62 and that this 
phosphorylation  is  important  for MycAmediated  regulation  of  genes  involved  in  cellular  senescence. 
We  show  that Myc  in  this way  suppresses RasAinduced  senescence, which  is one of  the barriers  for 
tumor development. This unique role of Cdk2 provides a potential therapeutical advantage to combat 
Myc and /or RasAdriven tumors. 




In  paper  II  we  identify  a  new  E3  ubiquitin  ligase,  SCFFBXO28  that  was  found  to  target  Myc  for 
ubiquitylation and to play a critical role in regulation of Myc function in tumor progression. Our data 
further  suggest  that  SCFFBXO28  plays  an  important  role  in  transmitting  Cdk  activity  to Myc  function 
during  the  cell  cycle,  emphasizing  the CdkAFBXO28AMyc  axis  as  a potential molecular drug  target  in 
MycAdriven cancers. 




In paper III we show that Myc interacts with the tumor suppressor protein von Hippel Lindau (VHL) 
which is part of an E3 ubiquitin ligase complex. VHL was found to promote ubiquitylation of Myc in a 
nonAproteolytic fashion. We showed that VHL associates together with Myc at a subset of Myc target 
genes throughout the genome and activate or repress the expression of bound genes with functions in 
cancer  development,  gene  expression, metabolism  and  other  function. We  also  found  that  VHL  and 
Myc bind to the MYC locus and regulate the MYC gene expression. Our data reveal novel functions and 
new modes of regulation of two of the most important oncoproteins and tumor suppressor proteins in 
human  cancer,  cAMyc  and  VHL,  respectively. We  anticipate  that  this work will  have  preclinical  and 
potential clinical implications for cancer biology and treatment