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Elucidation of New Phosphorylation Site of the EWS/ATF1 Fusion Oncoprotein in Clear Cell Sarcoma

Award Number: R03CA262935
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Elucidation of New Phosphorylation Site of the EWS/ATF1 Fusion Oncoprotein in Clear Cell Sarcoma - Abstract Clear cell sarcoma (CCS) is an aggressive bone and soft tissue cancer of young adults. It is caused by gene fusions between EWS (Ewing’s sarcoma oncogene) and ATF1 (activating transcription factor) or CREB (cAMP-responsive element binding protein), giving rise to chimeric oncoproteins consisting of the N-terminal EWS domain fused to a C-terminal half of truncated ATF1 and CREB domains. The chimeric EWS/ATF1 and EWS/CREB oncoproteins are potent transcription factors that bind to CRE (cAMP-responsive element) via the ATF1 and CREB domains. Normal human ATF1 and CREB are activated by stimulus-induced phosphorylation, in which ATF1 at Ser63 and CREB at Ser133 are phosphorylated by protein kinase A (PKA) or related kinases in response to various growth factors and hormones. In contrast, the molecular mechanism through which the transcription function of EWS/ATF1 and EWS/CREB is regulated remains unknown. The primary reason for this problem is the fact that truncated ATF1 and CREB domains fused to EWS do not contain these canonical Ser63 and Ser133 PKA-mediated phosphorylation sites. However, we recently identified the conserved new phosphorylation sites in the chimeric oncoproteins of ATF1 at Ser198 and CREB at Ser271. Intriguingly, we found that HIPK2 (homeodomain interacting protein kinase 2), but not PKA, phosphorylates EWS/ATF1 at Ser198 of the ATF1 domain and suppresses the transcription of c-FOS, one of the key EWS/ATF1 target genes driving aggressive cell proliferation of CCS. Indeed, EWS/ATF1 can be phosphorylated at Ser198 of the ATF1 domain in human CCS cells. Furthermore, we preliminary identified candidates of ATF1 Ser198 phosphatases. Thus, we have found two new potential reversible regulators of EWS/ATF1 oncoprotein through Ser198 phosphorylation. We will test our hypothesis that the phosphorylation status of EWS/ATF1 at Ser198 determines the EWS/ATF1 transcription activity on key target genes responsible for aggressive proliferation of CCS cancer cells. We will characterize the phosphorylation and dephosphorylation of EWS/ATF1 at Ser198 associated with its transcription function and CCS malignant phenotype. As ATF1 and CREB contain highly conserved phosphorylation sites, we anticipate the same regulatory mechanism of the EWS/CREB fusion oncoprotein via Ser271 phosphorylation in the truncated CREB domain. HIPK2 as well as Ser198 ATF1 phosphatases characterized in this proposal can be a new molecular target for more selective and effective inactivation of these fusion oncoproteins in CCS. 1


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: 2026 ( Subtotal = -$2,779 )
2026	2023	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Cancer Biology Research	000	2	12/3/2025	NON-COMPETING CONTINUATION	-$2,779
														Subtotal = -$2,779

Issue Date FY: 2023 ( Subtotal = $76,000 )
2023	2023	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Cancer Biology Research	000	2	6/8/2023	NON-COMPETING CONTINUATION	$76,000
														Subtotal = $76,000

Issue Date FY: 2022 ( Subtotal = $76,000 )
2022	2022	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Cancer Biology Research	000	1	7/22/2022	NEW	$76,000
														Subtotal = $76,000

Grand Total All Awards = $149,221

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Elucidation of New Phosphorylation Site of the EWS/ATF1 Fusion Oncoprotein in Clear Cell Sarcoma

Award Number: R03CA262935

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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