Division of Molecular Carcinogenesis
The Netherlands Cancer Institute
1989 Searle Scholar
The Cell Cycle
E2F transcription factorsThe mammalian cell division cycle is regulated by the sequential activation of several cyclins that bind and activate a group of cyclin-dependent kinases (cdks). An important target of the cdks is the retinoblastoma family of growth-inhibitory proteins that includes the retinoblastoma protein pRb and the related p107 and p130. These proteins, collectively known as pocket proteins, inhibit cell proliferation by sequestration of a number of growth-promoting proteins, the most prominent of which is a cellular transcription factor named E2F. To study cell cycle regulation by pocket proteins, we have isolated cDNAs for cellular proteins that interact with p107 and 130. Two of these cDNAs encode novel E2Fs: E2F-4 interacts with both p107 and p130, E2F-5 only with p130. An important goal for the near future is to dissect the functional differences between the various E2F family members.
Adenovirus transforming proteinsAdenovirus E1A proteins disrupt cell cycle control by binding to a number of cellular proteins. We have cloned two novel cellular proteins that interact with E1A, named BS69 and mUBC9. The latter encodes a novel member of the family of ubiquitin conjugating enzymes (UBCs). These proteins are involved in the ubiquitin-mediated protein degradation pathway. The function of mUBC9 in the mammalian cell cycle is currently being investigated.
The c-myc proto oncogeneThe product of the c-myc proto oncogene, MYC, encodes a transcription factor that is essential for normal cell cycle progression. Little is known about the regulation of MYC activity during the cell cycle. We have shown previously that the retinoblastoma protein-related p107 can form a specific complex with the MYC transactivation domain, causing inhibition of MYC transactivation. We are currently investigating which components of the cell cycle machinery are direct targets of c-Myc.
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