Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response

Abstract

, glutamic acid-and leucine-rich protein-1 (PELP1) is a scaffolding oncogenic protein that functions as a coregulator for a number of nuclear receptors. p53 is an important transcription factor and tumor suppressor that has a critical role in DNA damage response (DDR) including cell cycle arrest, repair or apoptosis. In this study, we found an unexpected role for PELP1 in modulating p53-mediated DDR. PELP1 is phosphorylated at Serine1033 by various DDR kinases like ataxia-telangiectasia mutated, ataxia telangiectasia and Rad3-related or DNAPKc and this phosphorylation of PELP1 is important for p53 coactivation functions. PELP1-depleted p53 (wild-type) breast cancer cells were less sensitive to various genotoxic agents including etoposide, camptothecin or c-radiation. PELP1 interacts with p53, functions as p53-coactivator and is required for optimal activation of p53 target genes under genomic stress. Overall, these studies established a new role of PELP1 in DDRs and these findings will have future implications in our understanding of PELP1's role in cancer progression. Cell Death and Differentiation (2014) 21, 1409-1418; doi:10.1038/cdd.2014.55; published online 2 May 2014 p53 is considered as the guardian of genomic integrity and has an important role in initiating cellular response to various genomic stresses such as cell cycle arrest, senescence, DNA repair and apoptosis.1,2 Loss of p53 or mutations in p53 is observed in 450% of the cases of all cancers.3-5 Stabilization of p53 upon genomic stress and activation of its transcription functions are vital for its central role in the DNA damage/ genomic stress response and in its tumor-suppressive functions.6,7 Upon genomic stress, p53 is stabilized and activated because of a decreased interaction with its E3-ligase MDM2.8 Activated p53 then upregulates expression of target genes, such as p21/WAF1, GADD45, PUMA and NOXA, all of which are important in the cellular decisions for cell cycle arrest or apoptosis. Post-translational modifications of p53, including phosphorylation, acetylation, ubiquitinylation and methylation, 10-12 and interactions with several cofactors 13,14 have a critical role in the p53-mediated transcriptional response to the DNA damage response (DDR). Proline-, glutamic acid-and leucine-rich protein-1 (PELP1), a large multi-domain protein, modulates a number of biological processes and several pathways including estrogen signaling, and cancer progression. 17 It promotes cell proliferation by enhancing G1 to S phase progression via its interactions with the pRb/E2F pathway.25 PELP1 localizes to the nucleolus and has an important role in ribosomal biogenesis.26 PELP1 signaling is also implicated in apoptosis and differentiation, and PELP1 functions as a coactivator of RXR homodimers and RXR-PPAR heterodimers.27 Although PELP1's role in both cell proliferation and differentiation is evident, it is not known how PELP1 would affect p53-mediated DDR functions and whether PELP1 status would affect sensitivity to various genomic stresses.In this study,...

PELP1 Overexpression in the Mouse Mammary Gland Results in the Development of Hyperplasia and Carcinoma

“…Since coregulators are shared by multiple transcription factors and some of these coactivation functions may promote tumor suppression, and tumor promotion may be delayed until such pathways are inactivated. In support of this, our recent study suggested that PELP1 also functions as co-activator of tumor suppressor p53 and such activation may counteract PELP1 oncogenic functions and could contribute to long latency (45). …”

PELP1: Structure, biological function and clinical significance

“…DNA damage induced kinases (ATM, ATR) phosphorylates PELP1 on Ser1033. (Nair et al 2014). Phosphorylation of PELP1 seems to be the key regulatory mechanism that controls its localization, modulates its interactions with adaptor proteins, alter its stability depending on the site of phosphorylation and may function as a sensor of the physiologic signals by connecting them to nuclear receptors.…”

“…In addition to nuclear receptors and transcription factors, PELP1 is shown to interact with several key players of cell cycle progression, including retinoblastoma protein (pRb) (Balasenthil and Vadlamudi 2003), cyclin-dependent kinase 2 (CDK2), and -4 (CDK4) (Nair et al 2010a), E2F1 (Krishnan et al 2015) and p53 (Krishnan et al 2015) (Nair et al 2014). PELP1 also interacts with several kinases including c-Src (Chakravarty et al 2010a), phosphoinositide 3-kinase (PI3K) (Dimple et al 2008), epidermal growth factor receptor (EGFR) (Vadlamudi et al 2005c), integrin-linked kinase (ILK1) (Chakravarty et al 2010a), mechanistic target of rapamycin (mTOR) (Gonugunta et al 2014b) and GSK3β (Sareddy GR et al 2015).…”

Amino-terminal residues of ΔNp63, mutated in ectodermal dysplasia, are required for its transcriptional activity

“…Being discovered much earlier, p53 is the best studied member of the family, showing a very complex gene activation program from autophagy [26], mitochondria and ROS regulation [27], metabolism [28], DNA damage repair [29,30], stemness and lineage determination [31]. Despite so many years, many questions remain still open in order to fully understand the biological role and function of this transcription factor.…”