Our pervious data demonstrated that overexpression of HSG exhibits a profound anti-proliferative and proapoptotic effects in vivo and in vitro. To further confirm the role of HSG in controlling cell growth, we performed this study using primary human T-cells and B cell lymphoma cell line BJAB. In primary human T cells, activation-induced HSG downregulation precedes cells entry into cell cycle. Blocking of HSG downregulation by either rapamycin (mTOR inhibitor), LY 294002 (PI3Kinase inhibitor), A443654 (AKT inhibitor) or anti-IL-2 antibody resulted in the blockage of cell proliferation. The inhibition of HSG downregulation by the inhibitors was not a consequence of cell the cycle blockage, since the cell cycle blockers, aphidicolin and nocodozole) blocked the cell cycle without preventing downregulation of HSG. Currently we are investigating the mechanism of HSG degradation by mTOR pathway. In B-cell lymphoma cell line BJAB, overexpression of HSG suppressed serum-evoked cell proliferation. Knockdown of HSG in BJAB cells showed enhancement in cell growth. In elucidating the mechanism of HSG-mediated growth suppression, we have shown that HSG interacts with Ras resulting in the inhibition of Ras-Raf-MEK-ERK pathway. Current focus of this project is to delineate the structure-function relationship of HSG with regards to its anti-proliferative properties in relation to its mitochondrial localization. We are also studying the status of HSG in proliferating T cells from young and old mice to determine whether HSG is responsible for sluggish proliferative response observed in T cells from old mice.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000451-05
Application #
8736568
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$294,781
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Chen, Kuang-Hueih; Dasgupta, Asish; Ding, Jinhui et al. (2014) Role of mitofusin 2 (Mfn2) in controlling cellular proliferation. FASEB J 28:382-94