Friday, October 3, 2025 10/3/2025

Role of elF2a phosphorylation and ER stress in hypoxia tolerance and tumor growth

Award Number: R01CA094214
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2002
PERIOD OF PERFORMANCE END DATE: 05/31/2018

Group Awards By:

View Award Description

Role of elF2a phosphorylation and ER stress in hypoxia tolerance and tumor growth - DESCRIPTION (provided by applicant): Hypoxia and nutrient deprivation conditions are dynamic features of the tumor microenvironment that contribute to cancer progression and resistance to treatment. We have previously shown that hypoxic stress activates the endoplasmic reticulum (ER) kinase PERK thereby inducing phosphorylation of the translation initiation factor eIF2a on ser51. Later, we also demonstrated that the nutrient-sensing kinase GCN2, similarly activates eIF2 phosphorylation in solid tumors in response to both amino acid and glucose deprivation. Phosphorylation of eIF2a not only reduces energy expensive processes such as global translation, but also creates an environment that promotes the more efficient translation of stress-responsive genes, such as ATF4, a transcription factor that upregulates genes involved in adaptation to ER stress. The phosphorylation of eIF2a and the upregulation of ATF4 represent a common mechanism activated by different cellular stresses, thereby being termed the Integrated Stress Response (ISR). Disruption of the ISR in tumor cells dramatically affects their proliferation and survival under stress and their ability to grow tumors in vivo. Together, our data support a model in which transformed cells activate the ISR in vivo as an adaptive response to oxygen and nutrient deprivation stress and that disruption of this pathway at several steps compromises cellular survival under stress and tumor growth. The overall hypothesis of this proposal is that the ISR transducers PERK and GCN2 which are activated under conditions of tumor microenvironmental stress, activate pathways that lead to increased cell survival and angiogenesis and contribute to metastasis. To test this hypothesis, we propose the following three specific aims: In Aim 1, we will determine the role of the cyclin-dependent kinase inhibitor p21 in mediating cell-cycle arrest and survival in response to hypoxia and nutrient deprivation in ISR-proficient and deficient cells. In Aim 2, we will investigate the role of GCN2 and PERK in angiogenesis using in vitro angiogenesis models. We will also identify mediators of angiogenesis downstream of GCN2 and PERK using antibody arrays and sucrose sedimentation analysis of actively translated mRNAs. In Aim 3, we will use transgenic mouse models of fibrosarcoma which will be crossed to GCN2+/+ and GCN2-/- mice. Angiogenesis and metastasis will be investigated in these models. Completion of these aims will establish whether the ISR is a critical targets of tumorigenesis and metastasis and define the mechanism of such an activity. Inhibitors of PERK and GCN2 are being actively pursued by the PI's lab and by pharmaceutical companies. Therefore, such data could facilitate rapid movement of lead compounds into preclinical animal testing phase.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2018 ( Subtotal = -$4,178 )
2018	2016	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	14	9/25/2018	EXTENSION WITH OR WITHOUT FUNDS	-$4,178
														Subtotal = -$4,178

Issue Date FY: 2016 ( Subtotal = $279,366 )
2016	2016	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	14	5/12/2016	EXTENSION WITH OR WITHOUT FUNDS	$279,366
														Subtotal = $279,366

Issue Date FY: 2015 ( Subtotal = $279,366 )
2015	2015	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	13	6/24/2015	NON-COMPETING CONTINUATION	$279,366
														Subtotal = $279,366

Issue Date FY: 2014 ( Subtotal = $270,985 )
2014	2014	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	12	8/5/2014	NON-COMPETING CONTINUATION	$270,985
														Subtotal = $270,985

Issue Date FY: 2013 ( Subtotal = $262,604 )
2013	2013	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	11	6/14/2013	NON-COMPETING CONTINUATION	$262,604
														Subtotal = $262,604

Issue Date FY: 2012 ( Subtotal = $279,366 )
2012	2012	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	10	8/8/2012	COMPETING CONTINUATION	$279,366
2012	2011	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	9	8/8/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $279,366

Issue Date FY: 2011 ( Subtotal = $248,411 )
2011	2011	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	9	6/7/2011	NON-COMPETING CONTINUATION	$248,411
														Subtotal = $248,411

Issue Date FY: 2010 ( Subtotal = $257,195 )
2010	2010	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	8	6/1/2010	NON-COMPETING CONTINUATION	$257,195
														Subtotal = $257,195

Issue Date FY: 2009 ( Subtotal = $257,484 )
2009	2009	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	7	5/29/2009	NON-COMPETING CONTINUATION	$257,484
														Subtotal = $257,484

Issue Date FY: 2008 ( Subtotal = $260,472 )
2008	2008	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	6	5/16/2008	NON-COMPETING CONTINUATION	$260,472
														Subtotal = $260,472

Issue Date FY: 2007 ( Subtotal = $269,215 )
2007	2007	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	5	6/26/2007	COMPETING CONTINUATION	$269,215
														Subtotal = $269,215

Issue Date FY: 2005 ( Subtotal = $238,569 )
2005	2005	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Cause and Prevention Research	000	4	5/25/2005	NON-COMPETING CONTINUATION	$238,569
														Subtotal = $238,569

Issue Date FY: 2004 ( Subtotal = $238,569 )
2004	2004	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Cause and Prevention Research	000	3	6/8/2004	NON-COMPETING CONTINUATION	$238,569
														Subtotal = $238,569

Issue Date FY: 2003 ( Subtotal = $237,832 )
2003	2003	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Cause and Prevention Research	000	2	6/26/2003	NON-COMPETING CONTINUATION	$237,832
														Subtotal = $237,832

Issue Date FY: 2002 ( Subtotal = $233,966 )
2002	2002	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Cancer Cause and Prevention Research	000	1	6/20/2002	NEW	$233,966
														Subtotal = $233,966

Grand Total All Awards = $3,609,222

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Role of elF2a phosphorylation and ER stress in hypoxia tolerance and tumor growth

Award Number: R01CA094214

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2002

PERIOD OF PERFORMANCE END DATE: 05/31/2018

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer