# Regulation of Histone Deacetylases by mAKAP Signalosomes

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $16,934

## Abstract

Cardiac hypertrophy is the primary compensatory response of the heart to chronic stress. In disease, this non-
mitotic growth is accompanied by changes in gene expression, ion fluxes and metabolism that affects cardiac
contractility, and induces myocyte apoptosis and interstitial fibrosis. At the core of these physiological changes
is the altered transcription of key genes that mediate cardiac remodeling. Hence, understanding the mechanism
that regulate gene expression has attracted significant attention for clinical applications. Histone deacetylases
(HDAC) of the class IIa family (including HDAC4, 5 and 9) are signal-responsive regulators of gene expression
and are thought to repress cardiac hypertrophy via protein-protein interactions with transcription factors.
Phosphorylation by pro-hypertrophic signaling enzymes such as Protein kinase D (PKD) stimulates the nuclear
export of HDACs, thereby promoting the gene transcription required for cardiac hypertrophy. In contrast, acute
beta-adrenergic stimulation and activation of Protein Kinase A induces nuclear retention of HDAC5. However,
chronic beta-adrenergic stimulation, as seen in disease, results in a PKA-mediated increased in nuclear export,
suggesting PKA is responsible for both retention and export of HDAC under different conditions We propose
that chronic beta-adrenergic stimulation induces the expression of the salt-inducible kinase I (SIK1), another
HDAC kinase. Our funded parent proposal finds the A-Kinase anchoring protein mAKAPb is required for the
short term PKA regulation of HDAC5. Preliminary evidence suggests that mAKAPb also mediates the nuclear
export of HDAC5 seen in chronic beta-adrenergic stimulation, presumably via the association with SIK1. The
goal of this supplement is to test the hypothesis that the binding of SIK1 by mAKAPb is required for the
regulation of HDAC5 and induction of cardiac hypertrophy. This will be tested by developing reagents
to disrupt the association by defining the domain on mAKAPb that is required for SIK1 association
(Aim1), investigate the importance of mAKAPb-SIK1 binding for PKA-mediated SIK1 protein stabilization
and export of HDAC5 (Aim2), and determine the functional significance of complex formation for
induction of cardiac hypertrophy (Aim3).

## Key facts

- **NIH application ID:** 10236920
- **Project number:** 3R01HL146111-03S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Kimberly L Dodge-Kafka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $16,934
- **Award type:** 3
- **Project period:** 2018-12-15 → 2021-09-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236920

## Citation

> US National Institutes of Health, RePORTER application 10236920, Regulation of Histone Deacetylases by mAKAP Signalosomes (3R01HL146111-03S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10236920. Licensed CC0.

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