Transcription Factors as Oncogenes

Another class of oncogenes are those that encode nuclear proteins, or transcription factors. Two examples of this class of oncogenes are AP-1 and c-myc. Activator protein-1 (AP-1) consists of Fos family members (c-fos, fos B, Fra 1, and Fra 2) and Jun family members (c-jun, jun B, and jun D), which can dimerize through a lucine rich proteidprotein interaction domain known as the leucine zipper (84). Fos-jun heterodimers are the most active, jun-jun homodimers are weakly active, and fos-fos homodimers form only in extremely rare circumstances. These dimers bind to AP-1 DNA binding sites, which are also called the tumor promoter TPA-responsive element (TRE) or glucocorticoid response element (GRE). AP-1 can be activated by ionizing and ultraviolet irradiation, DNA damage, cytokines, and oxi-dative and cellular stresses (85).

AP-1 has several functions in the cell, including the promotion of cell proliferation and metastasis. AP-1 is a nuclear target for growth factor-induced signaling such as the aforementioned EGFR-mediated kinase cascade. AP-1 -regulated genes include genes necessary for metastasis, and invasion like the MMPs matrilysin and stromelysin, as well as collagenase two proteins that aid in cell migration through connective tissue.

Deregulation of c-myc often occurs either by gene rearrangement or amplification in human cancers. Here again the hematologic cancers are instructive. In Burkitt's lymphoma, a frequent reciprocal translocation between chromosomes 8 and 14 leads to juxtaposition-ing of the myc gene adjacent to the Ig heavy chain promoter/enhancer complex, causing uncontrolled expression and production of the myc protein (86). Translocations between chromosomes 2 and 8 and between 8 and 22 also occur and involve other immunoglobulin producing gene complexes. In all cases the overproduction of myc results in uncontrolled cell proliferation.

Myc overexpression also occurs in solid tumors, but is usually the result of gene amplification (87). The oncogenic potential of c-myc has been studied most widely as it pertains to the development of colon cancer. Both c-myc RNA and protein are overexpressed at the early and late stages of colorectal tumorigene-sis. The cause for this overexpression is still unknown, but a strong possibility may be that it is regulated by the APC pathway. The APC tumor suppressor gene is mutated in approximately 90% of colorectal tumors, both sporadic and inherited forms. AF'C will be discussed in detail in the "tumor suppressor" section of this chapter.

He et al. (88) found that when APC expression was induced in stably transfected APC~7^ colon cancer cells (usingan inducible metallo-thionine promoter linked to the APC gene), they observed a time-dependent decrease in the RNA and protein levels of c-myc. This suggested that c-myc may be regulated by AF'C through the j3-catenin/T-cell factor-4 (Tcf-4) transcription complex. They also showed that constitutive expression of mutant j3-catenin (mutated so that it is insensitive to APC) in embryonic kidney cells resulted in a significant increase of c-myc expression. Analysis of the c-myc gene revealed two possible Tcf-4 transcription factor binding sites. Mobility shift assays demonstrated that Tcf-4 binds to both of the potential binding sites, leading to c-myc gene expression. Expression of dominant-negative Tcf-4 in HCT116 (mutant j3-catenin) or SW480 (mutant AF'C) reduced endogenous levels of c-myc (88).

The c-myc protein binds to DNA through its basic, helix-loop-helix/leucine zipper domain. Many target genes of c-myc have been identified that are involved in cell growth and proliferation. Some of these genes include ODC, cell cycle genes cyclins A, E, and Dl, as well as cdc2, cdc25, eukaryotic initiation factor 4E (eIF4E), heat shock protein 70 (hsp70), and dihydrofolate reductase. Overexpression of c-myc may therefore affect the transcription of these genes, thus promoting hyperpro-liferation and tumorigenesis.

C-myc is also found to be amplified in pro-leukemia and small cell lung cancer. The c-myc protein requires dimerization with Max to initiate transcription, and Max homodimers serve as an antagonist of transcription. The formation of Mad-Max dimers also suppresses transcription. It is also interesting to note that the full oncogenic potential of c-myc relies on cooperation with other on-cogenes like ras.

4.1.6 Cytoplasmic Proteins. Bcl-2 is an example of a cytoplasmic oncogene that has anti-apoptotic potential. Increased production of bcl-2 protein is seen in a variety of tumor types and is associated with poor prognosis in carcinomas of the colon and prostate. The function of bcl-2 is explained in detail in the "apopto-sis" section of this chapter.

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