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Study the Mechanism of Retinoblastoma Protein Mediated Androgen Receptor Transcriptional Repression Activity on DNA Replication

Award Number: R01CA211350
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary While AR has been extensively characterized as a transcriptional activator, it was recently reported to function as a transcriptional repressor to suppress a subset of genes. Significantly, through AR ChIP-seq and transcriptome profiling in prostate cancer cells we have found that the directly AR-repressed genes are highly enriched for DNA replication function and majority of those genes were consistently increased in CRPC clinical samples. We then discovered that this direct transcriptional repression activity of AR was mediated by androgen-stimulated recruitment of hypophosphorylated Rb. Androgens is also known to stimulate growth by further AR transcriptional activation of genes driving lipid and sterol synthesis, and other metabolic functions, with subsequent cyclin dependent kinase activation and Rb hyperphosphorylation. Overexpression of AR in prostate cancer cells could overcome this growth stimulatory effect. These findings demonstrate that AR has an Rb-dependent anti-proliferative function, which may be compromised in CRPC cells with Rb-deficiency and could be enhanced by blocking Rb phosphorylation. The objective of this proposal is to determine the function roles of AR recruitment of Rb in regulating transcription of DNA replication genes and cell cycle progression of PCa tumor cells (specific aim 1), to determine the molecular basis for AR interaction with hypophosphorylated Rb and characterize the distinct Rb complex recruited by AR to the suppression sits (specific aim 2), and to conduct a genome wide analysis to identify Rb dependent AR suppression sites and determine the mechanism of actions and function roles of these sites in prostate cancer cells (specific aim 3).


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: 2024 ( Subtotal = -$5,500 )
2024	2021	UNIVERSITY OF MASS AT BOSTON	100 WILLIAM T MORRISSEY BLVD	DORCHESTER	MA	02125	SUFFOLK	USA	Cancer Biology Research	000	5	2/7/2024	NON-COMPETING CONTINUATION	-$5,500
														Subtotal = -$5,500

Issue Date FY: 2021 ( Subtotal = $348,844 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Cancer Biology Research	000	5	8/17/2021	NON-COMPETING CONTINUATION	$348,844
														Subtotal = $348,844

Issue Date FY: 2020 ( Subtotal = $348,844 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Cancer Biology Research	000	4	8/21/2020	NON-COMPETING CONTINUATION	$348,844
														Subtotal = $348,844

Issue Date FY: 2019 ( Subtotal = $338,378 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Cancer Biology Research	000	3	8/12/2019	NON-COMPETING CONTINUATION	$338,378
														Subtotal = $338,378

Issue Date FY: 2018 ( Subtotal = $348,844 )
2018	2018	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Cancer Biology Research	000	2	8/6/2018	NON-COMPETING CONTINUATION	$348,844
														Subtotal = $348,844

Issue Date FY: 2017 ( Subtotal = $348,844 )
2017	2017	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Cancer Biology Research	000	1	9/25/2017	NEW	$348,844
														Subtotal = $348,844

Grand Total All Awards = $1,728,254

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Study the Mechanism of Retinoblastoma Protein Mediated Androgen Receptor Transcriptional Repression Activity on DNA Replication

Award Number: R01CA211350

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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