Int6 has been implicated in the development of breast cancer because it was first identified from a genetic screen in which the mouse mammary tumor virus (MMTV) was used as an insertional mutagen. MMTV insertions in int6 lead to C-terminal truncations in the protein, thus removing its PCI domain (Proteasome-COP9-lnitiation factor), which is found frequently among proteins that interact with the 26S proteasome. With the support of our current grant, we have investigated the molecular functions of Int6 by using a genetic model system the fission yeast Schizosaccharomyces pombe. Our data support a hypothesis in which Int6 regulates mitotic abnormalities and chromosome segregation by controlling the proper assembly and localization of the proteasome. We propose that Int6 acts as a tumor suppressor. When Int6 is inactivated, the proteasome becomes inactive, thus leading to the accumulation of mitotic regulators blocking proper cell division control and chromosome segregation. In this renewal, our goals are to further define how Int6 controls proteasome assembly and localization in the S. pombe system and to examine whether the functions of Int6 as revealed in S. pombe can also function in humans and play roles during tumorigenesis.
Our Aim 1 is to determine whether S. pombe Int6 can allow the proteasome to more selectively and efficiently degrade given substrates by acting through another evolutionary conserved protein called Moe1, which binds proteins such as Cdc48 and APC (Anaphase Promoting Complex) that are known to bind polyubiquitinated proteasome substrates.
In Aim 2 we will study how Int6 influences proteasome localization by examining the possibility that Int6 in S. pombe regulates the F-actin cytoskeleton via a component of the Arp2/3 complex called Arc21, which may mediate the proper formation of transport vesicles.
In Aim 3, we will directly examine in human mammary epithelial cells whether Int6 also regulates the proteasome to influence mitosis and chromosome segregation and whether its inactivation can transform these cells and form tumors in nude mice. We believe that understanding the regulation of the proteasome by Int6 can lead to the design of better cancer diagnosis and more focused cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090464-09
Application #
8019462
Study Section
Special Emphasis Panel (ZRG1-ONC-U (90))
Program Officer
Hildesheim, Jeffrey
Project Start
2001-04-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
9
Fiscal Year
2011
Total Cost
$264,170
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Young, Evelin; Zheng, Ze-Yi; Wilkins, Angela D et al. (2014) Regulation of Ras localization and cell transformation by evolutionarily conserved palmitoyltransferases. Mol Cell Biol 34:374-85
Zheng, Ze-Yi; Chang, Eric C (2014) A bimolecular fluorescent complementation screen reveals complex roles of endosomes in Ras-mediated signaling. Methods Enzymol 535:25-38
Zheng, Ze-Yi; Xu, Lizhong; Bar-Sagi, Dafna et al. (2012) Escorting Ras. Small GTPases 3:236-9
Zheng, Z-Y; Cheng, C-M; Fu, X-R et al. (2012) CHMP6 and VPS4A mediate the recycling of Ras to the plasma membrane to promote growth factor signaling. Oncogene 31:4630-8
Suo, J; Snider, S J; Mills, G B et al. (2011) Int6 regulates both proteasomal degradation and translation initiation and is critical for proper formation of acini by human mammary epithelium. Oncogene 30:724-36
Hartig, Sean M; He, Bin; Long, Weiwen et al. (2011) Homeostatic levels of SRC-2 and SRC-3 promote early human adipogenesis. J Cell Biol 192:55-67
Cabrera, Rodrigo; Suo, Jinfeng; Young, Evelin et al. (2011) Schizosaccharomyces pombe Arc3 is a conserved subunit of the Arp2/3 complex required for polarity, actin organization, and endocytosis. Yeast 28:495-503
Cheng, Chiang-Min; Li, Huiling; Gasman, Stephane et al. (2011) Compartmentalized Ras proteins transform NIH 3T3 cells with different efficiencies. Mol Cell Biol 31:983-97
Cheng, Chiang-Ming; Chang, Eric C (2011) Busy traveling Ras. Cell Cycle 10:1180-1
Otero, Joel H; Suo, Jinfeng; Gordon, Colin et al. (2010) Int6 and Moe1 interact with Cdc48 to regulate ERAD and proper chromosome segregation. Cell Cycle 9:147-61

Showing the most recent 10 out of 21 publications