A splice variant of cyclin D2 regulates cardiomyocyte cell cycle through a novel protein aggregation pathway

Sun, Qian; Zhang, Feixiong; Wafa, Karim; Baptist, Timothy; Pasumarthi, Kishore B.S.

doi:10.1242/jcs.047738

Cited by 17 publications

(30 citation statements)

References 45 publications

(57 reference statements)

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“…Tissue lysates from pooled E11.5 or neonatal hearts were generated as previously described (40). Clear 96-well microtiter plates (Nunc, New York, NY; cat.…”

Section: Methodsmentioning

confidence: 99%

“…A-21426) or goat anti-mouse Western blot analyses. Tissue lysates were prepared from pooled ventricles of different developmental stages, run on 12.5% polyacrylamide gels, and transferred to nitrocellulose membranes as previously described (40). For detecting the small 3-kDa ANP peptide, 16.5% gels were used and transfer was performed using Tris-tricine buffer (Bio-Rad) for shorter time periods.…”

Section: Methodsmentioning

confidence: 99%

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Atrial natriuretic peptide inhibits cell cycle activity of embryonic cardiac progenitor cells via its NPRA receptor signaling axis

Hotchkiss

Feridooni

Baguma-Nibasheka

et al. 2015

American Journal of Physiology-Cell Physiology

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(NPRs), which can either activate guanylyl cyclase (NPRA and NPRB) or inhibit adenylyl cyclase (NPRC) to modulate intracellular cGMP or cAMP, respectively. During cardiac development, ANP serves as an early maker of differentiating atrial and ventricular chamber myocardium. As development proceeds, expression of ANP persists in the atria but declines in the ventricles. Currently, it is not known whether ANP is secreted or the ANP-NPR signaling system plays any active role in the developing ventricles. Thus the primary aims of this study were to 1) examine biological activity of ANP signaling systems in embryonic ventricular myocardium, and 2) determine whether ANP signaling modulates proliferation/differentiation of undifferentiated cardiac progenitor cells (CPCs) and/or cardiomyocytes. Here, we provide evidence that ANP synthesized in embryonic day (E)11.5 ventricular myocytes is actively secreted and processed to its biologically active form. Notably, NPRA and NPRC were detected in E11.5 ventricles and exogenous ANP stimulated production of cGMP in ventricular cell cultures. Furthermore, we showed that exogenous ANP significantly decreased cell number and DNA synthesis of CPCs but not cardiomyocytes and this effect could be reversed by pretreatment with the NPRA receptorspecific inhibitor A71915. ANP treatment also led to a robust increase in nuclear p27 levels in CPCs compared with cardiomyocytes. Collectively, these data provide evidence that in the developing mammalian ventricles ANP plays a local paracrine role in regulating the balance between CPC proliferation and differentiation via NPRA/ cGMP-mediated signaling pathways. embryonic heart; ANP; natriuretic peptide receptors; gene expression; cardiac progenitor cells; cardiomyocytes; lineage tracking; knockin mice; cell proliferation and differentiation ATRIAL NATRIURETIC PEPTIDE (ANP) is a 28 amino acid peptide that is synthesized and stored primarily in secretory granules of atrial cardiomyocytes in the adult heart. Ligand binding of ANP to its cognate natriuretic peptide receptors (NPRs) can either activate guanylyl cyclase (NPRA and NPRB) or inhibit adenylyl cyclase (NPRC) to modulate intracellular cGMP or cAMP, respectively. The primary stimulus for ANP secretion from atrial cardiomyocytes is mechanical stretch of the atrial wall (15). In addition to mechanical stimuli, several vasoconstrictor peptides including endothelin-1 (ET-1) (36) and angiotensin II (9), as well as a variety of neurohormones, growth factors, and cytokines, have been shown to modulate natriuretic peptide secretion (10). Once in the circulation, ANP acts in a true endocrine fashion by stimulating NPRA receptors in the kidneys, adrenal cortex, and vasculature to regulate fluid homeostasis and maintain blood pressure via diuretic, natriuretic and vasorelaxant effects (29). In the ventricles of the adult heart, the levels of ANP protein are normally ϳ1,000-fold lower than in the atria and secretory granules are rarely observed (31).In contrast to the adult heart, developmental stud...

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“…Tissue lysates from pooled E11.5 or neonatal hearts were generated as previously described (40). Clear 96-well microtiter plates (Nunc, New York, NY; cat.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Atrial natriuretic peptide inhibits cell cycle activity of embryonic cardiac progenitor cells via its NPRA receptor signaling axis

Hotchkiss

Feridooni

Baguma-Nibasheka

et al. 2015

American Journal of Physiology-Cell Physiology

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“…It is known that the human and mouse truncated Cyclin D2 splice variant, D2SV, with a unique C terminus is also observed in cytoplasmic foci. 38 Our results indicate a possible cytoplasmic role of Cyclin Dbb/d variants during germline proliferation in O. dioica, with preferred localizations adjacent to syncytial nuclei during S-phase entry.…”

Section: Asynchronously Proliferating O Dioica Germ Nuclei Have a DImentioning

confidence: 57%

“…Under conditions of nutrient restriction, increased levels of mouse cytoplasmic D2SV splice variants 40 exert a suppressive role on cell cycle progression by sequestering key cell cycle regulators including cyclin D2, CDK4, Cyclin B and possibly p27. 36,38,39 Previously we have shown that the survival MAPK p38-MSK-1 signaling pathway is activated in the O. dioica mitotic germline during nutrient-dependent GA or when TOR signaling is inhibited. 8 Common responses to stress-induced p38 activation are cell cycle arrest or apoptosis.…”

Section: Altered Cyclin D Variant Expression In Response To Mapk P38 mentioning

confidence: 99%

“…36 It is expressed in the mouse ovary 37 and sequesters CDK4 and p27 in the cytoplasm, possibly targeting them for ubiquitin-dependent protein degradation. 36,38,39 Human Cyclin D2SV is overexpressed in some primary human brain tumors. 37 The D2SV splice variant is responsive to nutrient-dependent signaling and is upregulated during nutrient limitation.…”

Section: Introductionmentioning

confidence: 99%

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Co-expressed Cyclin D variants cooperate to regulate proliferation of germline nuclei in a syncytium

2015

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The role of the G1-phase Cyclin D-CDK 4/6 regulatory module in linking germline stem cell (GSC) proliferation to nutrition is evolutionarily variable. In invertebrate Drosophila and C. elegans GSC models, G1 is nearly absent and Cyclin E is expressed throughout the cell cycle, whereas vertebrate spermatogonial stem cells have a distinct G1 and Cyclin D1 plays an important role in GSC renewal. In the invertebrate, chordate, Oikopleura, where germline nuclei proliferate asynchronously in a syncytium, we show a distinct G1-phase in which 2 Cyclin D variants are co-expressed. Cyclin Dd, present in both somatic endocycling cells and the germline, localized to germline nuclei during G1 before declining at G1/S. Cyclin Db, restricted to the germline, remained cytoplasmic, co-localizing in foci with the Cyclin-dependent Kinase Inhibitor, CKIa. These foci showed a preferential spatial distribution adjacent to syncytial germline nuclei at G1/S. During nutrient-restricted growth arrest, upregulated CKIa accumulated in arrested somatic endoreduplicative nuclei but did not do so in germline nuclei. In the latter context, Cyclin Dd levels gradually decreased. In contrast, the Cyclin Dbb splice variant, lacking the Rb-interaction domain and phosphodegron, was specifically upregulated and the number of cytoplasmic foci containing this variant increased. This upregulation was dependent on stress response MAPK p38 signaling. We conclude that under favorable conditions, Cyclin Dbb-CDK6 sequesters CKIa in the cytoplasm to cooperate with Cyclin Dd-CDK6 in promoting germline nuclear proliferation. Under nutrient-restriction, this sequestration function is enhanced to permit continued, though reduced, cycling of the germline during somatic growth arrest.

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Splice Variants and Phosphorylated Isoforms of Cyclin D1 in Tumorigenesis

Diehl

Knudsen

2017

D-Type Cyclins and Cancer

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A splice variant of cyclin D2 regulates cardiomyocyte cell cycle through a novel protein aggregation pathway

Cited by 17 publications

References 45 publications

Atrial natriuretic peptide inhibits cell cycle activity of embryonic cardiac progenitor cells via its NPRA receptor signaling axis

Atrial natriuretic peptide inhibits cell cycle activity of embryonic cardiac progenitor cells via its NPRA receptor signaling axis

Co-expressed Cyclin D variants cooperate to regulate proliferation of germline nuclei in a syncytium

Splice Variants and Phosphorylated Isoforms of Cyclin D1 in Tumorigenesis

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