Dual role of the AP-1 family members in Abelson induced Tumour Formation: cooperation versus antagonism

The AP-1 transcription factor complex relays extracellular signals into changes in the transcription and expression of many cellular genes. Signals affecting AP-1 activity include growth factors, cytokines, tumour promoters and carcinogens. Jun-family members (c-Jun, JunB and JunD) homodimerize within the family or heterodimerize with c-Fos or ATF family members to form AP-1. Fetuses lacking JunB die on embryonic day E8.5 to E10. The introduction of a junB transgene in the junB-/- background fully rescues the embryonic lethality. However, all rescued mice develop a myeloproliferative disease due to an age-dependent myeloid-specific loss of junB transgene expression. Disease progression to blast crisis is observed in 10-20% of the mice mimicking the pathology of human chronic myeloid leukaemia (CML). In contrast overexpression of JunB in mice does not lead to an obvious phenotype. However, increased JunB expression leads to a decreased proliferation and fibroblasts and prevents oncogenic transformation by Ras and Src in these cells. These findings identify JunB as a negative regulator of cell proliferation and as a potential tumour suppressor. In contrast to JunB, c-Jun is considered a proto-oncogene. A role for c-Jun in transformation has been clearly established in the past and has been linked to tumour development in several tissues. Increased levels of c-Jun and AP-1 activity were also described in human CML cells. More than 95% of human CML is associated with the Philadelphia chromsome, a translocation of chromosomes 9 and 22, which results in a chimeric gene, the bcr-abl oncogene or Abelson oncogene. The corresponding gene product displays constitutive tyrosine kinase activity and is located in the cytoplasm in contrast to the nuclear c-abl protein. The Abelson oncogene is also found in 30% of patients suffering from acute lymphoid leukaemia (ALL). In this project we intend to investigate the role of the proto-oncogene c-Jun and the potential tumour suppressor JunB for Abelson induced transformation in lymphoid and myeloid cells using a combination of in vitro and in vivo experiments. If c-Jun/JunB turns out to be important in human myelo- or lymphoproliferative disease, activation of JunB expression or inhibition of c-Jun will be new thereapeutical options in the treatment of these diseases.

Tumour cells generally express high levels of the AP-1 transcription factor family. We have investigated he expression of AP-1 factors in human leukaemia and found a characteristic pattern. Leukemic cells of B lymphoid origin show a lack of expression or only a weak expression of the AP-1 family member JunB, whereas all other family members are expressed at high levels. Subsequently we characterised JunB as a growth inhibitor and tumor suppressor for B lymphoid cells. Upon malignant transformation B lymphoid cells have to acquire the ability to overcome growth inhibition by JunB. This process leads to subsequent alterations within the leukemic cells. The cells loose the expression of the cell cycle inhibitor p16 and start to express high levels of the cell cycle kinase cdk6. Hence, the loss of JunB leads to an accelerated proliferation of the transformed B lymphoid cells that - as a consequence - allows the cells to behave more aggressive and to form leukaemia significantly faster. This process is irreversible and can not be overcome by re-expressing JunB. C-Jun is an important counter-player of JunB. C- Jun has been shown to promote tumour formation and to regulate cell death (apoptosis) in some tumour types. We investigated the effects of c-Jun for B lymphoid leukaemia. We found that loss of c-Jun indeed impairs transformation and impairs the ability of the tumour cells to form leukaemia in mice. This effect is not based on differences in apoptosis, but the consequence of an altered cell cycle regulation. C-Jun induced the expression of the cell cycle kinase Cdk6 and accelerates cell proliferation. Our study pinpoints for he first time the interplay of AP-1 transcription factors and the cell cycle kinase Cdk6. This connection is of particular importance, since Cdk6 inhibitors are developed as novel cancer therapeutics.