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    Research Grants Awarded

    P-TEFB, A NOVEL THERAPEUTIC TARGET FOR HUMAN BREAST CANCER

    Study Section:
    Tumor Cell Biology II

    Scientific Abstract:
    HEXIM1, a nuclear protein whose expression is induced in differentiated cells, has been shown to play an important role in controlling breast cell growth and transformation. As an inhibitor of cell growth, the expression of HEXIM1 is down-regulated by estrogens and decreased in breast tumors. An antigrowth function of HEXIM1 is further illustrated by the demonstration that overexpression of HEXIM1 in breast cancer cells suppresses cell proliferation as well as anchorage-independent growth. Conversely, inhibiting HEXIM1 expression leads to increased cell growth. HEXIM1 has recently been shown to interact with the human positive transcription elongation factor b (P-TEFb) in a process mediated by the 7SK snRNA. Consisting of CDK9 and cyclin T, P-TEFb stimulates transcriptional elongation by phosphorylating RNA polymerase II. HEXIM1 is a specific, 7SK-dependent inhibitor of the P-TEFb kinase. Accumulating evidence has implicated the HEXIM1:7SK:P-TEFb snRNP as a key signal integration point whereby different physiological stimuli converge and affect gene transcription by modulating the amount of P-TEFb sequestered in this complex and thus the levels of active P-TEFb in the cell. P-TEFb is not only the principal associated factor and target of HEXIM1; it is also a specific target of two CDK inhibitors, flavopiridol and CYC202 (aka R-Roscovitine or Seliciclib), which have shown promising anti-cancer effects through induction of apoptosis. Thus, P-TEFb warrants further investigation as a potential therapeutic target for human breast cancer. To determine whether the observed function of HEXIM1 in breast cells can be attributed to its regulation of P-TEFb, we will examine whether the estrogen-mediated HEXIM1 down-regulation can activate the kinase and transcriptional activities of P-TEFb in breast epithelial cells. In addition, we will employ methods to directly alter the nuclear P-TEFb level to investigate a possible role for P-TEFb in promoting malignant transformation of breast cells. Finally, we plan to further explore the connection between P-TEFb inactivation by the CDK inhibitors and the induction of apoptosis in breast cancer cells. We will examine whether the HEXIM1-mediated inhibition of P-TEFb produces a similar apoptotic effect and whether several key proteins involved in controlling apoptosis are similarly affected by HEXIM1 and the pharmacological inhibitors of P-TEFb. In summary, the proposed studies will help determine the roles of P-TEFb and HEXIM1 in mammary carcinogenesis and may reveal new therapeutic avenues for combating this cancer.

    Lay Abstract:
    A nuclear protein called HEXIM1 has recently been shown to have an anti-growth effect in breast epithelial cells. Treatment of cells with estrogens can cause a decrease in the expression of HEXIM1. On the other hand, the HEXIM1 level is the lowest in breast tumors and highest in surrounding normal tissues. An antigrowth function of HEXIM1 is further illustrated by the demonstration that overexpression of HEXIM1 in breast cells suppressed cell proliferation and anchorage-independent growth, one of the hallmarks of malignantly transformed cells. Conversely, inhibiting HEXIM1 expression led to increased cell growth. The target for HEXIM1 has recently been identified as the human positive transcription elongation factor b (P-TEFb). Consisting of CDK9 and cyclin T, P-TEFb stimulates transcription by phosphorylating RNA polymerase II, the molecular machine responsible for the transcription process. HEXIM1 functions as a specific inhibitor of P-TEFb through interacting with and inactivating the P-TEFb kinase. The sequestration of cellular P-TEFb by its inhibitor HEXIM1 has been proposed to serve as a key signal integration point whereby different physiological stimuli converge and affect gene transcription by modulating the levels of active P-TEFb in the cell. Not only is P-TEFb inhibited by HEXIM1, it is also a specific target of two CDK inhibitors, flavopiridol and CYC202, which have shown promising anti-cancer effects through induction of programmed cell death. For these reasons, we believe it is important to further investigate P-TEFb as a potential therapeutic target for human breast cancer. In this grant proposal, we plan to determine whether the antigrowth function of HEXIM1 in breast cells can be attributed to its regulation of P-TEFb. We will also employ methods to directly alter the nuclear P-TEFb level to investigate a possible role for P-TEFb in promoting malignant transformation of breast cells. Finally, we plan to further explore the connection between P-TEFb inactivation by the CDK inhibitors and the induction of programmed cell death in breast cancer cells. We will examine whether the HEXIM1-mediated inhibition of P-TEFb produces a similar effect and whether several key proteins involved in controlling programmed cell death are similarly affected by HEXIM1 and the pharmacological inhibitors of P-TEFb. In summary, the proposed studies will help determine the roles of P-TEFb and HEXIM1 in mammary carcinogenesis and may reveal new therapeutic avenues for combating this cancer.