The Role of HAP Kinases in Breast Cancer


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

1992-1993

FUNDING AMOUNT

599172.0 USD

ABSTRACT

TECHNICAL ABSTRACT We propose to study the regulation and function of a novel family of protein kinases, the heat stress-activated protein (HAP) kinases, breast tumor pathophysiology. HAP kinases normally participate in the cellular response to environmental stress where they phosphorylate, among other things, c-Jun, a protooncogene-encoded transcription factor that regulates gene expression in response to numerous stimuli, including mitogens. c-Jun may participate in mammary cell differentiation. In certain tumor cells, HAP kinases display a broader sensitivity to extracellular stimuli and can be activated by mitogens. In addition, HAP kinases may regulate a second mitogen-and heat shock-regulated protein kinase, mitogen-activated protein kinase-activated protein (MAPKAP) kinase-2. MAPKAP kinase-2 can phosphorylate hsp27, a polypeptide whose phosphorylation correlates with mammary tumor cell growth arrest. Taken together, these data suggest a role for HAP kinases in mammary cell growth. What extracellular stimuli or transformation events in mammary cells activate HAP kinases? Can HAP kinases activate MAPKAP kinase-2 hsp27 kinase activity? What effect do HAP kinases have on mammary cell proliferation? Accordingly, we will perform the following studies: (1) assess the mitogen/constitutive activation of HAP kinases in a panel of breast tumor cell lines; (2) characterize HAP kinase activators by yeast two hybrid cloning and biochemical purification; and (3) determine the role of HAP kinases in mitogenesis, using stable overexpression in breast tumor cells of wild-type and mutant HAP kinases. More... »

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