Molecular BIology of Cancer Topics

Immediate Early Genes

Treatment of serum-starved (normal) cells with serum, growth factors, or the tumor promoter TPA results in the induction of gene expression. The induced genes are classified according to the time at which they are induced.

Immediate early (IE), also known as early response or competence genes) are expressed in the first few minutes, their mRNA induction being very rapid and transient (lasts only a few hours). They are expressed during G0/G1, i.e. before the onset of S phase.

Protein synthesis is not required for their mRNA expression; rather, their transcription is induced by post-translational modification of existing transcription factors. Both their mRNA and protein products have short lives.

Fos, jun and myc are immediate early genes that encode transcription factors necessary for cell division. For example, blocking fos expression by antisense blocks the induction of other inducible genes, and blocks DNA synthesis and cells division in response to serum or growth factors. Fos, jun and myc are proto-oncogenes, and their oncogenes encode proteins that are constitutively overexpressed.

Fos/Jun

The sequence in the c-fos gene promoter that binds the transcription factors TCF (Elk) and Serum Response Factor (SRF) is known as the serum response element (SRE).

The c-fos proto-oncogene contains an SRE in its promoter, and a ATTTA sequence (AUUUA in mRNA) that makes the mRNA unstable and short lived. The v-fos oncogene lacks this sequence, therefore v-fos has a much longer half life than c-fos.

Fos protein synthesis leads to repression of c-fos transcription.

c-jun is another immediate early gene, although some c-jun mRNA and protein is always present, even in the abscence of serum. There is a rapid and transient increase in Jun mRNA and protein in response to serum. TPA induces Jun protein expression even in the absence of serum.

Jun is regulated by phosphorlation. Map kinase-catalyzed phosphorylation of Ser 63 and Ser 73 activates Jun, while phosphorylation at Thr 231, Ser 243 or Ser 249 by GSK inactivates Jun. Dephosphorylation of Thr 231, Ser 243 and Ser 249 by a phosphatase increases DNA binding. Experimental mutation of Ser 63 and Ser 73 to alanine abolishes Jun activity. Activation of protein kinase C by TPA decreases phosphorylation of the Thr 231, Ser 243 and Ser 249, thus allowing Jun activity.

The v-jun oncogene is carried by the acutely transforming retrovirus avian sarcoma virus 17, and lacks the amino acids 40 to 67 in c-jun (known as the d region).

Jun/Fos dimmers form the AP-1 transcription factor, binding to eahc other through a leucine zipper. The basic regions of jun and fos then bind cooperatively the AP-1 target site (TRE). The TRE sequence is a symmetrical palyndrome.

Fos, Jun and related proteins can form dimers other than Fos/Jun: Fos/JunB, Fos/JunD, Fra1/Jun, FosB/Jun, Jun/Jun. Fos does not dimerize with itself. The FO/Jun heterodimers are the most stable, bind TRE stronger, and inducer higher transcriptional transactivation. The Jun/Jun homodimers are the least stable, with weaker TRE binding and lower transcriptional transactivation. Fos is not functional in the absence of Jun, but Jun is functional (although at a lower level) in the absence of Fos. Therefore, AP-1 activity seems to be controlled by the amount of Fos.

The jun promoter has an AP-1/TRE site, thus Jun upregulates its own transcription.

Myc

Myc is a transcription factor with a basic region followed by a helix-loop-helix-leucine zipper motif. It dimmerizes with another transcription factor, Max. Max/Max homodimmers exist, but Myc does not dimmerize with itself.

Max is essential to Myc function. In proliferating cells, all Myc is bound to Max. Myc is transiently expressed in normal cells, whereas Max is long lived.

Myc/Max binds to the concensus sequence CACGTG. Myc overexpression activates CACGTG-dependent transcription, while Max overexpression represses it. Phosphorylation of Max/Max decreases binding to CACGTG (?).

Myc is required for cell cycle progession. A c-myc antisense oligonucleotide inhibits entry into S phase but not progress from G0 to G1 (Heikkila et. al. Nature 328:445; 1987).

The cdc25 cell cycle phosphatase is an important target gene of Myc/Max. The cdc25 gene promoter contains three Myc/Max binding sites. Myc increases cdc25 expression. cdc25 increases cell division, and its overexpression is oncogenic.

There are several sources of myc oncogenes. The avian myelocymatosis virus 29 is a v-myc. myc is a target for the avian leukosis virus. Myc is overexpressed in many human tumors. Translocation between chromosomes 8 and 14 in Burkitt's lymphomma results in deregulation of Myc expression (controlled by the IgH promoter rather than the myc promoter). Myc genes are also amplified in many human tumors.

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