| Budget Amount *help |
¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 1999: ¥7,500,000 (Direct Cost: ¥7,500,000)
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| Research Abstract |
Activation of telomerase is a common and specific feature in more than 85% of all cancers. In addition to the reverse transcriptase subunit of telomerase (TERT), the E6 gene of "high risk" human papillomavirus and the c-myc oncogene have been known to activate telomerase. In order to clarify the mechanisms activating telomerase, we examined the actions of these genes in activating telomerase, and elucidated the following points :
l. Both HPV16 E6 and c-myc activate telomerase by inducing the expression of TERT.
2. Neither E6 nor c-myc can activate telomerase in primary human fibroblasts.
3. In primary human mammary epithelial cells (HMEC), E6 can activate telomerase without increasing Myc, while E7 can increase Myc level but cannot activate telomerase. Expression of E6 together with E7 can activate telomerase stronger than E6 alone can.
4. With a yeast three hybrid system, cDNAs of novel cellular proteins that can bind to E6/E6AP complexes were isolated, and antisera against some of the proteins were raised.
From these results, we led the following hypotheses :
l. E6 enables the transcription factor Myc to access TERT locus by changing its chromatin structure.
2. In HMEC expressing E6 and E7, E6 and E7 can strongly activate telomerase by opening the chromatin structure and increasing Myc level, respectively.
3. E6/E6AP complexes might enhance degradation of a putative DNA binding protein(s) that can recruit proteins such as histone deacetylases.
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