Date of Award

2012-01-01

Degree Name

Master of Science

Department

Biological Sciences

Advisor(s)

Robert Kirken

Abstract

Tyrosine kinases are an essential component of cell signal transduction pathways, many of which promote cellular proliferation. However, when a tyrosine kinase is aberrantly activated or its negative regulation is lost, the result can be malignancy. In humans, 90 tyrosine kinases are present and of these, 51 have been linked to a malignancy through mutation or overexpression. Janus kinase 3 (JAK3) is one such kinase that upon hyperactivation, due to a somatic mutation, has been linked to cancer including its substrate, signal transducer and activator of transcription (STAT5). Few studies have investigated the role of JAK3/STAT5 pathways in hematopoietic cancers such as leukemia and lymphoma, nor whether health disparities exist among different groups with respect to these types of cancer and effectors. This is one of the first studies where multiple signaling molecules were studied in a large cohort of patients with

cancer. This study suggests that multiple proteins, including JAK3 and STAT5, are activated in different cancers. Multikinase inhibitors may represent a viable treatment option for patients displaying activation of multiple proteins, and a clinically approved JAK3 inhibitor needs to be developed. Using a peptide library a putative JAK3 consensus peptide substrate was identified. Of the 181 proteins "mined" as possible JAK3 substrates many may also represent a therapeutic target for uncoupling JAK3 dependent cancers. For example, our results implicate reciprocal activation of JAK3 and NPM-ALK in anaplastic large-cell lymphoma. Indeed, many of these proteins require further study and to define their pathways, which many be pivotal in therapeutic intervention in certain hematological malignancies.

Language

en

Provenance

Received from ProQuest

File Size

163 pages

File Format

application/pdf

Rights Holder

Damaris Rosado

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