Inhibition of the transcription factor AP-1 in cervical cancer

AP-I is a dimeric transcription factor comprised primarily of Jun and Fos family proteins, that regulates numerous genes involved in cell proliferation, differentiation and oncogenesis. The expression of AP-I is shown to play an important role in many human cancers and plays a key role in the regulation of the E6 and E7 oncoproteins of high-risk Human Papillomaviruses (HPV) that are etiologically associated with cervical cancer. The c-Jun and Jun B components of AP-I were shown to be expressed at higher levels in cervical cancer patients compared to nonnal patient tissue while Jun D levels were largely unchanged. To define the role of AP-I in cervical cancer, the effect of inhibiting AP-I actvity was determined using a dominantnegative deletion mutant T AM67. CaSki cervical cancer cells with a doxycycline inducible T AM67 demonstrated that inhibition of AP-I activity and expression resulted in an altered cell morphology, a significant decrease in cell proliferation and inhibition of colony formation. This was accompanied by a slower progression of T AM67 expressing cells through the cell cycle, with an accompanying increase in G21M phase. An increase in the expression of the cell cycle regulatory protein, p21 CIPI, was observed that appeared independent of p53 expression. siRNA directed at inhibiting individual AP-I components showed that Jun B was an important regulator of CaSki cell proliferation. These results suggest that AP-I is involved in the cell proliferation and tumourigenic phenotype of cervical cancer cells, such as CaSki cells, possibly via a direct repression of cell cycle regulator p21 CIP1

Grantor dc:publisher.institution

Division of Medical Biochemistry

Year dc:date.issued

2007

Author dc:creator

• Maritz, Michelle Frances

Advisor dc:contributor.advisor

• Leaner, Virna D

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/11427/3138

OAI identifier oai:identifier

oai:open.uct.ac.za:11427/3138