As the protein constituents of oncogenic pathways are rapidly becoming defined and, consequently, as cancer therapies become more pathway- specific, means for defining the specific oncogenic pathways activated in individual malignancies on routinely processed tissue samples, in a clinical rather than research setting, will be an essential part of the pathologic evaluation of tumor tissue. Presently, the ability of the anatomic pathologist to determine which oncogenic pathways are active in individual tumors is highly incomplete. One major methodologic gap is caused by the inability to directly assess protein kinase and phosphatase activity in routinely processed tumor tissue. Although changes in protein phosphorylation are invariant features of all oncogenic pathways, and account for thousands of molecular events in cells, few efforts have been made to introduce methods for direct detection of protein phosphorylation in routinely processed cancer tissue. The goal of the proposed studies is the development of an immunohistochemical method for detection of protein phosphorylation in tumor tissue. We will utilize antibodies which specifically detect the phosphorylated versions of key proteins in oncogenic/mitogenic signal transduction pathways. This approach is technically straightforward but methodologically powerful, since it is immediately adaptable to normally processed tissue samples in any pathology laboratory, and will fill a major gap in the molecular evaluation of malignant tissue samples. Our studies to date which reveal Cdk-phosphorylated histone H1 to be a novel immunohistochemical proliferation marker, suggest the untapped potential of this methodology.
| Good, Paul F; Alapat, Daisy; Hsu, Amy et al. (2004) A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzheimer's disease. J Neurochem 91:716-36 |
| Kafanas, Antonis; Wang, Beverly Y; Kalir, Tamara et al. (2003) Immunohistochemical visualization of histone H1 phosphorylation in squamous intraepithelial lesions of the gynecologic tract. Hum Pathol 34:166-73 |
