To all:
Sorry for late hour respond. It is not easy to get PC from my daughters, like getting $ from skinflint!
First my apologize for using this tread for GERN discussion. Andrew, my only intention is constructive discussions. On this thread almost all participants have better background knowledge (correlating to other threads) on bt than I have and I will appreciate any input.
Cell article is written in more details (and less experimental work on decoding activator protein sequence; MIT used combinatorial genomic database with disclosed data ,partial sequence, for yeast EST2 protein. Opposite to this Gern isolate this protein, sequence it , and combine with human genomic database plus additional sequencing) and actually it describe some proteins (hTRT = hEST2) as telomerase subprotein activator.
As I suspected (Isip thread) the postulation of the additional mechanism is likely and open:
Cell:>> Although we have found a general correlation between hEST2 mRNA levels and assayable telomerase activity, the present experiments do not demonstrate that these two manifestations of hEST2 gene expression are always present in some constant, predictable ratio. This leaves open the possibility that other mechanisms besides the presently observed modulation of hEST2 mRNA levels may intervene to modulate telomerase activity.<<
Generaly I am not concern on *telomerase activity modulation* side effects. Probably the telomerase reactivity in kidney cells is one think to consider very closely:
Cells:>> In contrast, the reappearance of telomerase enzyme activity when transformed cells escape from crisis or when tumors progress toward malignancy may in many cases be explained mechanistically by the derepression of hEST2 mRNA expression. As reported here, in cell cultures, this derepression occurs in both transformed embryonic kidney cells and lymphocytes when they emerge from crisis and begin to exhibit telomerase activity. Our work does not address whether the enhanced hEST2 RNA expression is achieved at the transcriptional or posttranscriptional level.<<
Definitely both article pointed out that reexpresion of the hTRT (hEst2) mRNA is RATE-LIMITING STEP in telomerase activity. Main protein and hRT are expressed at constant level in mortal and immortal cells line.
One things needs to be noted: Half-life time of the hTRT mRNA is only few hours [Cell: experiment on HL60 ,promyelocytic leukemia, cells differentiation induced with all-trans retinoic acid show that initial hTRT mRNA level decrease rapidly while telomerase activity decline at much slower rate (~24 hr is half-life enzymatic activity)].
This suggest that better inhibitor of the telomerase activity will probably be compound which interact on mechanism of DNA elongation, than on mRNA or *activator protein receptor* competition. Discovery of the mechanism which cause the reexpresion of the hTRT (or mRNA) is even better target for cancer cells proliferation.
More basic and difficult question is:
At the bottom line, who will have patent on this discovery and what will be protected? I do not have any second thought that specific site (malignant tumor cells) telomerase inhibition will have impact on cancer therapy. This is preliminary discovery (basic) and further development (what trigger hTRT mRNA reapperance and by which mechanism) is story to come. Race started and who will reach end first? Merck is company to respect and will not easily (if at all) give-up patent right (license). Also, if I remember correctly, P&U have recently obtained FDA approval for HIV RT non-nucleoside inhibitor (not very potent), but they have library of the small compounds to look/screen for telomerase inhibitor.
GERN, by agreement (If I am correct) reserve RT RNA partial sequence (active part by their explanation) for in house drug discovery. This include vector, antisense, rybozime,... which target is RNA. Dr. Cech influence and contribution to discovery secure his position if this approach give positive results (RZYM).
For several days I am trying to contact my friend at RZYM, but no luck. She is oligonucleotide chemist, and in many case great help to me. Chapman article where he describe discovery 5'-5'-P1,P4-tetraphosphate linkage active rybozime may present good starting point for understanding how telomerase work. Only rybozime are RNA polymerase, and telomerase elongate DNA parts. This can be diference and difficulty.
Anyway, hRT RNA has TTAGGG motive and Univ. of Nebraska (parent # 5,643,890 ; Jul.1 97) describe simple synthetic phosphorothioate oligonucleotide(also deoxiribonucleotide) with this motive, and TTCGGG, as telomerase in-vitro inhibitor.
Sumary: Two strong group of science oriented researcher describe significant discovery in basic understanding of the telomerase activity. Many groups will follow, but someone will have advantage and proprietary right. I do not think (someone in Gern thread posted) that RNA/DNA genome data will not be patentable. Who will than communicate his discoveries to other? Where is than progress?
mz |
