Abstract
Activating mutations of RAS GTPase contribute to the progression of many cancers, including colorectal carcinoma. So far, attempts to develop treatments of mutant RAS-carrying cancers have been unsuccessful due to insufficient understanding of the salient mechanisms of RAS signaling. We found that RAS downregulates the protein ATG12 in colon cancer cells. ATG12 is a mediator of autophagy, a process of degradation and reutilization of cellular components. In addition, ATG12 can kill cells via autophagy-independent mechanisms. We established that RAS reduces ATG12 levels in cancer cells by accelerating its proteasomal degradation. We further observed that RAS-dependent ATG12 loss in these cells is mediated by protein kinases MAP2K/MEK and MAPK1/ERK2-MAPK3/ERK1, known effectors of RAS. We also demonstrated that the reversal of the effect of RAS on ATG12 achieved by the expression of exogenous ATG12 in cancer cells triggers both apoptotic and nonapoptotic signals and efficiently kills the cells. ATG12 is known to promote autophagy by forming covalent complexes with other autophagy mediators, such as ATG5. We found that the ability of ATG12 to kill oncogenic RAS-carrying malignant cells does not require covalent binding of ATG12 to other proteins. In summary, we have identified a novel mechanism by which oncogenic RAS promotes survival of malignant intestinal epithelial cells. This mechanism is driven by RAS-dependent loss of ATG12 in these cells.
| Original language | English |
|---|---|
| Pages (from-to) | 134-151 |
| Number of pages | 18 |
| Journal | Autophagy |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2 2018 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology
Cite this
Oncogenic RAS-induced downregulation of ATG12 is required for survival of malignant intestinal epithelial cells. / Yoo, Byong Hoon; Khan, Iman Aftab; Koomson, Ananda; Gowda, Pramod; Sasazuki, Takehiko; Shirasawa, Senji; Gujar, Shashi; Rosen, Kirill V.
In: Autophagy, Vol. 14, No. 1, 02.01.2018, p. 134-151.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Oncogenic RAS-induced downregulation of ATG12 is required for survival of malignant intestinal epithelial cells
AU - Yoo, Byong Hoon
AU - Khan, Iman Aftab
AU - Koomson, Ananda
AU - Gowda, Pramod
AU - Sasazuki, Takehiko
AU - Shirasawa, Senji
AU - Gujar, Shashi
AU - Rosen, Kirill V.
PY - 2018/1/2
Y1 - 2018/1/2
N2 - Activating mutations of RAS GTPase contribute to the progression of many cancers, including colorectal carcinoma. So far, attempts to develop treatments of mutant RAS-carrying cancers have been unsuccessful due to insufficient understanding of the salient mechanisms of RAS signaling. We found that RAS downregulates the protein ATG12 in colon cancer cells. ATG12 is a mediator of autophagy, a process of degradation and reutilization of cellular components. In addition, ATG12 can kill cells via autophagy-independent mechanisms. We established that RAS reduces ATG12 levels in cancer cells by accelerating its proteasomal degradation. We further observed that RAS-dependent ATG12 loss in these cells is mediated by protein kinases MAP2K/MEK and MAPK1/ERK2-MAPK3/ERK1, known effectors of RAS. We also demonstrated that the reversal of the effect of RAS on ATG12 achieved by the expression of exogenous ATG12 in cancer cells triggers both apoptotic and nonapoptotic signals and efficiently kills the cells. ATG12 is known to promote autophagy by forming covalent complexes with other autophagy mediators, such as ATG5. We found that the ability of ATG12 to kill oncogenic RAS-carrying malignant cells does not require covalent binding of ATG12 to other proteins. In summary, we have identified a novel mechanism by which oncogenic RAS promotes survival of malignant intestinal epithelial cells. This mechanism is driven by RAS-dependent loss of ATG12 in these cells.
AB - Activating mutations of RAS GTPase contribute to the progression of many cancers, including colorectal carcinoma. So far, attempts to develop treatments of mutant RAS-carrying cancers have been unsuccessful due to insufficient understanding of the salient mechanisms of RAS signaling. We found that RAS downregulates the protein ATG12 in colon cancer cells. ATG12 is a mediator of autophagy, a process of degradation and reutilization of cellular components. In addition, ATG12 can kill cells via autophagy-independent mechanisms. We established that RAS reduces ATG12 levels in cancer cells by accelerating its proteasomal degradation. We further observed that RAS-dependent ATG12 loss in these cells is mediated by protein kinases MAP2K/MEK and MAPK1/ERK2-MAPK3/ERK1, known effectors of RAS. We also demonstrated that the reversal of the effect of RAS on ATG12 achieved by the expression of exogenous ATG12 in cancer cells triggers both apoptotic and nonapoptotic signals and efficiently kills the cells. ATG12 is known to promote autophagy by forming covalent complexes with other autophagy mediators, such as ATG5. We found that the ability of ATG12 to kill oncogenic RAS-carrying malignant cells does not require covalent binding of ATG12 to other proteins. In summary, we have identified a novel mechanism by which oncogenic RAS promotes survival of malignant intestinal epithelial cells. This mechanism is driven by RAS-dependent loss of ATG12 in these cells.
UR - http://www.scopus.com/inward/record.url?scp=85038618532&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85038618532&partnerID=8YFLogxK
U2 - 10.1080/15548627.2017.1370171
DO - 10.1080/15548627.2017.1370171
M3 - Article
C2 - 28933585
AN - SCOPUS:85038618532
VL - 14
SP - 134
EP - 151
JO - Autophagy
JF - Autophagy
SN - 1554-8627
IS - 1
ER -