GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

Abstract

The GATA transcription factors consist of six family members, which bind to the consensus DNA-binding element, W-GATA-R, and are poorly characterized in the central nervous system (CNS). Using retroviral gene trapping on transgenic mouse glioma models, we identified GATA6 to be a novel tumor suppressor gene in glioblastoma multiforme. We now show GATA4, a family member of GATA6, to be expressed in the neurons and glia of normal murine and human embryonic and adult CNS. Silencing GATA4 in normal astrocytes did not alter their growth properties. In contrast, knockdown of Gata4 in p53 null non-transformed murine astrocytes induced transformation, with increased proliferation and resistance to chemotherapy or radiation-induced apoptosis. Furthermore, GATA4 expression was lost in a panel of human malignant astrocytoma cell lines. GATA4 overexpression in normal human and murine astrocytes resulted in a cell cycle block in G1 phase, with increased apoptosis. Mechanistically, GATA4 was a transcriptional inducer of the cyclin-dependent kinase inhibitor, p15INK4B, leading to the attenuation of cyclin D1. GATA4 expression was also induced by transforming growth factor-b, leading to the inhibition of astrocyte proliferation. Collectively, we show that GATA4 is expressed in the embryonic and adult CNS and acts as a negative regulator of astrocyte proliferation and growth.

Corticothalamic Projection Neuron Development beyond Subtype Specification: Fog2 and Intersectional Controls Regulate Intraclass Neuronal Diversity

“…FOG2 interacts with members of the Coup-tf and Gata families of transcription factors, forming transcriptional complexes with critical functions in the development of other organs (Tevosian et al, 2000; Ackerman et al, 2007). COUPTF1, COUPTF2, GATA2, and GATA4 are expressed in the developing cortex (Tripodi et al, 2004; Minegishi et al, 1999; Agnihotri et al, 2009), and multiple repeats of their consensus binding site sequences map to a highly conserved region upstream of Ctip2 (Figure 8 G), suggesting that these factors might interact with FOG2 in transcriptional complexes to regulate Ctip2 expression.…”

The transcription factor GATA4 is required for follicular development and normal ovarian function

“…Previously, GATA4 has been shown to act as a regulator of cell growth and proliferation in tissues other than the gonads (Agnihotri et al, 2009; Rojas et al, 2008; Singh et al, 2010; Trivedi et al, 2010; Zeisberg et al, 2005). To determine whether ovaries from conditional mutants have altered cell proliferation or apoptosis, we performed BrdU-labeling (Fig.…”

Transcription Factor GATA4 Inhibits Doxorubicin-induced Autophagy and Cardiomyocyte Death

“…In addition, it is possible that GATA4 regulates ATG genes through p53, a transcription factor able to trigger autophagy (61), and implicated in DOX-induced cardiomyocyte death (62). A potential interaction between GATA4 and p53 has been suggested in murine astrocytes (63), and the direct interaction and mutual antagonism between GATA1 and p53 has been confirmed in erythrocytes (64). These possibilities regarding the mechanisms whereby GATA4 inhibits autophagy remain largely speculative and need to be tested experimentally in future studies.…”