Gadd45 Stress Sensors in Malignancy and Leukemia

Abstract

Gadd45 proteins, including Gadd45a, Gadd45b and Gadd45g, have been implicated in stress signaling in response to physiological and environmental stress, including oncogenic stress, which can result in cell cycle arrest, DNA repair, cell survival, senescence, and apoptosis. The function of Gadd45 as a stress sensor is mediated via a complex interplay of physical interactions with other cellular proteins implicated in cell cycle regulation and the response of cells to stress, notably PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. Altered expression of Gadd45 has been observed in multiple types of solid tumors as well as in hematopoietic malignancies. Using genetically engineered mouse models and bone-marrow transplantation, evidence has been obtained indicating that Gadd45 proteins can function to either promote or suppress tumor development and leukemia; this is dependent on the molecular nature of the activated oncogene and the cell type, via engagement of different signaling pathways.

Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells

“…The enhanced expression of GADD45G in aged HSCs, and the finding that aged GADD45G-depleted HSCs show an increased self-renewal and accumulation , may indicate a role of GADD45G in HSC life span control. Further, the epigenetic inactivation of Gadd45g in many malignancies explains the inability of tumor cells to terminally differentiate (Liebermann et al, 2011). Further studies are warranted to utilize the GADD45G-mediated pathway to therapeutically switch misregulated self-renewal in cancer-initiating cells into differentiation.…”

“…GADD45G caught our interest because of its role as DNA-damage response and tumor suppressor gene that is epigenetically silenced in many malignancies (Liebermann et al, 2011). Moreover, GADD45G is upregulated in LT-HSCs of aged mice with reduced reconstitution ability (Rossi et al, 2005), and small hairpin RNA (shRNA)-mediated knockdown of GADD45G selected for aged HSCs with higher self-renewal potential .…”

Epigenetic regulation of mammalian sex determination

“…GADD45 mediates diverse cellular processes, such as DNA repair, apoptosis, cell cycle arrest and senescence (15,16). The GADD45 proteins also function in gene activation, by promoting DNA demethylation and MAPK signaling.…”

Polymorphisms in the p53 pathway genes and micronucleus occurrence in Chinese vinyl chloride-exposed workers

“…Both of these metabolites interact with DNA to form DNA adducts and induce errors during DNA and RNA synthesis. Previous studies showed that VC exposure physiological stress, as well as to have a role in development and carcinogenesis [9]. GADD45A induction following DNA damage is rapid, transient and dose-dependent.…”