- Title Information
- Title
- Genetic and Biochemical Analysis of the Grb10-Interacting GYF Protein 2 (GIGYF2): A Link Between the Insulin and Insulin-Like Growth Factor Hormonal Systems and Parkinson's Disease
- Name:
Personal
- Name Part
- Tsiaras, William G
- Role
- Role Term:
Text
- creator
- Origin Information
- Copyright Date
- 2010
- Physical Description
- Extent
- xiv, 211 p.
- digitalOrigin
- born digital
- Note
- Thesis (Ph.D. -- Brown University (2010)
- Name:
Personal
- Name Part
- Smith, Robert
- Role
- Role Term:
Text
- Director
- Name:
Personal
- Name Part
- Gruppuso, Philip
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Sedivy, John
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Guardavaccaro, Daniele
- Role
- Role Term:
Text
- Reader
- Name:
Corporate
- Name Part
- Brown University. BIOMED: Molecular Biology, Cell Biology, and Biochemistry
- Role
- Role Term:
Text
- sponsor
- Genre (aat)
- theses
- Abstract
- The insulin (IR) and insulin-like growth factor receptors (IGF-IR) are critical mediators of growth, development and survival. Given their immense biological significance, a complex system of intracellular molecules has evolved to facilitate precise regulation of these hormone receptors. The adaptor protein Grb10 is an important component of this regulatory system. Grb10 functions as a physiologic suppressor of IR and IGF-IR signaling. Recently, two Grb10-interacting proteins, GIGYF1 and GIGYF2, were identified based on their capacity to bind to the proline-rich region of Grb10. GIGYF1 forms a complex with Grb10 and activated IGF-IR, and can modulate receptor signaling. GIGYF2 exhibits similar affinity and specificity for Grb10, yet the biological significance and molecular function of this protein have not been established. As an initial approach to the analysis of GIGYF2, genetic data was examined for linkage of the GIGYF2 gene to human disease. This revealed significant association between GIGYF2 (PARK11 locus) and familial Parkinson's disease (PD). Using a candidate-gene analysis we investigated the involvement of GIGYF2 in PD. We identified GIGYF2 mutations in 4.8% of PD patients, indicating that mutations in GIGYF2 are a frequent cause of familial PD. To further explore the link between GIGYF2 and neurodegeneration and the involvement of GIGYF2 in growth and development, we disrupted the Gigyf2 gene in mice. Gigyf2-/- mice exhibit early postnatal lethality. Gigyf2+/- mice develop normally, but show evidence of age-dependent motor ataxia and neurodegeneration. MEFs from Gigyf2-/- animals show altered IGF-IR signaling, indicating that GIGYF2 may contribute to Grb10-receptor regulation. These findings support a causal role for GIGYF2 in PD, and establish the first link between a PD gene and the IGF system. To better define the function of GIGYF2 we further characterized GIGYF2 deficient cells. In the absence of GIGYF2, the cell cycle protein cyclin D1 is reduced as a result of increased degradation. Through biochemical analysis, we determined that GIGYF2 interacts with the CUL7-PARC-p53 complex and has the capacity to disrupt the SKP1-CUL7-FBXW8 ubiquitin ligase. These results provide a mechanism for GIGYF2- regulation of cyclin D1 degradation and suggest participation of the GIGYF2 protein in potential CUL7-PARC-p53 functions.
- Subject
- Topic
- GIGYF2
- Subject
- Topic
- GIGYF1
- Subject
- Topic
- Grb10
- Subject
- Topic
- IGF-IR
- Subject
- Topic
- insulin receptor
- Subject
- Topic
- Neurodegeneration
- Subject
- Topic
- PARK11
- Subject
- Topic
- CUL7
- Subject
- Topic
- Cyclin D1
- Subject
- Topic
- PARC
- Subject
- Topic
- p53
- Subject
- Topic
- SKP1
- Subject
- Topic
- FBXW8
- Subject (FAST)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/974506")
- Topic
- Insulin--Receptors
- Subject (FAST)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/1053693")
- Topic
- Parkinson's disease
- Record Information
- Record Content Source (marcorg)
- RPB
- Record Creation Date
(encoding="iso8601")
- 20111003
- Language
- Language Term:
Code (ISO639-2B)
- eng
- Language Term:
Text
- English
- Identifier:
DOI
- 10.7301/Z0445JQM
- Access Condition:
rights statement
(href="http://rightsstatements.org/vocab/InC/1.0/")
- In Copyright
- Access Condition:
restriction on access
- Collection is open for research.
- Type of Resource (primo)
- dissertations