The p53 tumor suppressor protein is a critical regulator of hematopoietic stem cell behavior

Abstract

In response to diverse stresses, the tumor suppressor p53 differentially regulates its target genes, variably inducing cell cycle arrest, apoptosis or senescence. Emerging evidence indicates that p53 plays an important role in regulating hematopoietic stem cell (HSC) quiescence, self-renewal, apoptosis and aging. The p53 pathway is activated by DNA damage, defects in ribosome biogenesis, oxidative stress and oncogene induced p19ARF upregulation. We present an overview of the current state of knowledge about p53 (and its target genes) in regulating HSC behavior, with the hope that understanding the molecular mechanisms that control p53 activity in HSCs and how p53 mutations affect its role in these events may facilitate the development of therapeutic strategies for eliminating leukemia (and cancer) propagating cells.

The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy

“…6,22,30,33,35,36,[38][39][40][41][42][43][44][45][46] Furthermore targeting of the bone marrow microenvironment and the cancer stem cells with combinations of these signal transduction inhibitors and chemotherapy may enhance cancer treatment. [32][33][34][35][36]47 There are also complicated interactions between p53 and PI3K/PTEN/Akt/mTOR, Raf/MEK/ ERK and other signaling and apoptotic pathways. [4][5][6][22][23][24]46,47 Some of these interactions may result in novel therapeutic targets.…”

“…[32][33][34][35][36]47 There are also complicated interactions between p53 and PI3K/PTEN/Akt/mTOR, Raf/MEK/ ERK and other signaling and apoptotic pathways. [4][5][6][22][23][24]46,47 Some of these interactions may result in novel therapeutic targets. [48][49][50][51][52][53] For example, Akt phosphorylates MDM-2 which regulates p53 stability.…”

Protecting the hedgerow: p53 and Hedgehog pathway interactions

“…46 In the absence of apparent stress, p53 can regulate stem cell renewal and quiescence. 47,48 The activation of low levels of constitutive stress or basal p53 expression can also regulate metabolism, such as by the enhancement of mitochondrial respiration. 49 Particularly with respect to metabolism, p53 has seemingly paradoxical roles that act to promote survival of cells.…”

Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy

“…11,20,21,31,32,[37][38][39][40][41][42][43]58,59,67,68 Furthermore, the p53 tumor suppressor is a common target of many chemotherapeutic drugs and can interact with many signaling pathways. [69][70][71][72] Approaches that combine prolongation of wild-type p53 activity may enhance the effects of chemotherapeutic drugs, either in the presence of absence of signal transduction inhibitors. [73][74][75][76][77][78] Elucidating the mechanisms of interaction of chemotherapy, p53 activators and signal transduction inhibitors and how they enhance cell death by various mechanisms may yield more effective therapy.…”