Regulation of the Multiple Functions of Msi1p/Cac3p

North Central College, Naperville IL

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Abstract

DESCRIPTION (provided by applicant): A single protein generally has a single function or a small number of closely related functions. Msi1p (also known as Cac3p) is a protein found in the yeast Saccharomyces cerevisiae that dramatically violates this generalization by having at least three widely diverse functions. The protein was originally identified genetically as a suppressor of the cytoplasmic RAS/cAMP signal transduction pathway in yeast. Additionally, Msi1p has also been found to be an essential subunit of the nuclear chromatin assembly complex. Finally, the human homologs of Msi1p were initially identified biochemically as proteins that physically associate with the product of the retinoblastoma tumor suppressor gene (pRB) and Msi1p itself has been demonstrated to be an essential mediator of transcriptional repression by pRB. Thus, Msi1p is a single small protein that participates in three biological activities that appear to be very different from one another. Over the next three years in this laboratory, undergraduate students will carry out a variety of genetic and biochemical experiments which will separate and characterize the three functions of Msi1p. Are these three functions truly distinct or are they cryptically related to one another in some subtle fashion that we have not yet appreciated? Furthermore, can Msi1p perform more than one of these functions at a given time or can a single Msi1 protein affect only one of these activities at any moment? Finally, our laboratory will build on some intriguing preliminary studies to investigate how these multiple functions are coordinately regulated in vivo. Our studies that separate, characterize and examine the regulation of the multiple functions of Msi1p will provide unique insights into the function of this protein. It is noteworthy that all three known functions of Msi1p directly impinge upon human health. The yeast Ras protein is functionally homologous to the human Ras proteins that are one of the most commonly activated proto-oncogenes in human cancers. Furthermore, pRB is a key human tumor suppressor protein that is part of a pathway believed to be disrupted in the majority of human cancers. Finally, chromatin assembly and epigenetic regulation is emerging as an important mechanism that becomes disregulated in cancers Taken together, the multiple functions of Msi1p place it at an extraordinary position in modern biology.