Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1999-08-18
2000-11-21
Schwartzman, Robert A.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 2431, 536 2433, 435325, 4352523, C12N 1512, C12N 510
Patent
active
061505153
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Intricate mechanisms regulate mRNA synthesis by control of initiation or elongation of transcription. An understanding of these mechanisms and the factors controlling these mechanisms would be important in designing therapeutic modalities for treating a variety of important medical conditions, including cancer and infection. For example, HIV-1 transcriptional elongation by Tat is essential for viral replication. Interruption of transcriptional elongation by Tat, therefore, would be highly desirable as a means for treating HIV-infected individuals.
Tat activation of HIV-1 transcription is mechanistically different from conventional activation of transcription by DNA sequence-specific transcription factors. First, most conventional activators affect transcription primarily through increasing the rate of initiation, although recent studies indicate that some prototype DNA sequence-specific transcription factors such as GAL4-VP16 can stimulate both initiation and elongation. In contrast, Tat predominantly stimulates the efficiency of elongation. Secondly, while most conventional activators interact with promoter or enhancer DNA, Tat interacts with the trans-acting responsive (TAR) RNA element. TAR is located at the 5' end of the nascent viral transcript and forms a stem-loop structure. The specific binding of Tat to TAR depends primarily upon the integrity of the bulge loop and immediately flanking sequences in the double-stranded RNA. Sequences in the apical loop of TAR are also important for Tat activation of transcription in vivo.
Control of transcriptional elongation thus has been recognized as an important step in gene regulation, but mechanisms regulating the efficiency of elongation, mediated by RNA polymerase II, have not been extensively studied. The necessity for strict control of elongation for proper gene regulation is further highlighted by the recent finding that an elongation factor, Elongin, is probably the functional target of the von Hippel-Lindau tumor suppressor protein.
SUMMARY OF THE INVENTION
The invention involves in one respect the identification, purification, and isolation of proteins, Tat-Stimulatory Factor protein, which are specifically required for Tat trans-activation. The invention also involves nucleic acid molecules encoding those proteins. The invention further involves the discovery and identification of kinases that bind the Tat-Stimulatory Factor proteins, which binding is believed important for TAT transcriptional elongation. The expression and biological activity of the proteins are necessary for transcriptional elongation, and alteration of the expression or biological activity of these proteins can be used to influence transcriptional activity, and thereby affect critical cellular processes.
The preferred nucleic acids of the invention are homologues and alleles of the coding region of the nucleic acid of SEQ ID NO: 1. The invention further embraces functional equivalents, variants, analogues and fragments of the foregoing nucleic acids and also embraces proteins and peptides coded for by any of the foregoing.
According to one particular aspect of the invention, an isolated nucleic acid molecule is provided. The molecule hybridizes under stringent conditions to a molecule consisting of the coding region of the nucleic acid sequence of SEQ ID NO:1 and it codes for a Tat-Stimulatory Factor protein. The invention further embraces nucleic acid molecules that differ from the foregoing isolated nucleic acid molecules in codon sequence due to the degeneracy of the genetic code. The invention also embraces complements of the foregoing nucleic acids. Preferred isolated nucleic acid molecules are those comprising the human cDNAs or genes corresponding to SEQ ID NO:1. Unique fragments of the foregoing molecules are specifically contemplated by the inventors.
The invention in another aspect involves expression vectors, and host cells transformed or transfected with such expression vectors, comprising the nucleic acid molecules described above. In o
REFERENCES:
Zhou and Sharp, The EMBO Journal, 14(2): 321-328 (1995).
Zhou and Sharp, Science, 274: 605-610 (1996).
Desai et al., Proc Natl Acad Sci USA, 88: 8875-8879 (1991).
Sharp Phillip A.
Zhou Qiang
Lacourciere Karen A
Massachusetts Institute of Technology
Schwartzman Robert A.
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