Two decades of a protooncogene HPIP/PBXIP1: Uncovering the tale from germ cell to cancer

Khumukcham, Saratchandra Singh; Manavathi, Bramanandam

doi:10.1016/j.bbcan.2021.188576

Cited by 18 publications

(14 citation statements)

References 71 publications

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“…20 Pbxip1 interacts with transport as well as regulatory proteins and indirectly affects transcription. 21 Proteome data did not show differential expression of mitochondrial transport proteins and respiratory chain complexes (Figure VII in the Data Supplement). Proteome data for sarcomere components, glycolysis, and amino acid metabolism did not show differential expression (Figure VIII in the Data Supplement).…”

Section: Resultsmentioning

confidence: 92%

“…40 Moreover, PBXIP1 regulates the activity of MAPK and mTOR signaling. 21 The function of Pbxip1 in the heart is largely unknown. In a prior genetic screen, the inhibition of MAPK signaling pathway proteins increased PBXIP1 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…20 Pbxip1 interacts with transport as well as regulatory proteins and indirectly affects transcription. 21 5B).…”

Section: Moderate Transcriptional Dysregulation In Prdm16 Csp1/wt Heartsmentioning

confidence: 98%

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Prdm16mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators

Kühnisch

Theisen

Dartsch

et al. 2023

Preprint

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Background: Mutation of the PRDM16 gene has been associated with human cardiomyopathy. The PRDM16 protein is a transcriptional regulator affecting cardiac development via Tbx5 and Hand1 regulating myocardial structure. Biallelic Prdm16 inactivation induces severe cardiac dysfunction with postnatal lethality and hypertrophy in mice. Early pathological events upon Prdm16 inactivation have not been explored. Methods: This study performed in depth pathophysiological and molecular analysis of male and female Prdm16csp1/wt mice carrying systemic, monoallelic Prdm16 gene inactivation. We systematically assessed early molecular changes with transcriptomics, proteomics, and metabolomics. Kinetic modelling of the cardiac metabolism was undertaken in silico with CARDIOKIN. Results: Prdm16csp1/wt mice are viable up to 8 months, develop hypoplastic hearts, and diminished systolic performance that is more pronounced in female mice. Prdm16csp1/wt hearts demonstrate moderate alterations of specific transcripts and protein levels with consistent upregulation of pyridine nucleotide-disulphide oxidoreductase domain 2 (Pyroxd2) and the transcriptional regulator pre B-cell leukemia transcription factor interacting protein 1 (Pbxip1). The strongest concordant transcriptional upregulation was detected for Prdm16 itself probably by an autoregulatory mechanism. Prdm16csp1/wt cardiac tissue showed reduction of metabolites associated with amino acid as well as glycerol metabolism, glycolysis, and tricarboxylic acid cycle. Global lipid metabolism was also affected with accumulation of triacylglycerides detected in male Prdm16csp1/wt hearts. In addition, Prdm16csp1/wt cardiac tissue revealed diminished glutathione (GSH) and increased inosine monophosphate (IMP) levels indicating oxidative stress and a dysregulated energetics, respectively. Metabolic modelling in silico suggested lowered fatty acid utilization in male and reduced glucose utilization in female Prdm16csp1/wt cardiac tissue. Conclusions: Monoallelic Prdm16 mutation restricts cardiac performance in Prdm16csp1/wt mice. Metabolic alterations precede transcriptional dysregulation in Prdm16csp1/wt cardiac tissue. Female Prdm16csp1/wt mice develop a more pronounced phenotype indicating a sexual dimorphism at this early pathological window. This study suggests that metabolic dysregulation is an early event in PRDM16 associated cardiac pathology.

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Section: Resultsmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Prdm16mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators

Kühnisch

Theisen

Dartsch

et al. 2023

Preprint

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“…Hematopoietic pre-B cell leukemia transcription factor (PBX)interacting protein (HPIP/PBXIP1) is involved in embryogenesis and oncogenesis (28). HPIP overexpression has been shown in many cancers, such as breast cancer, lung cancer, and colorectal cancer, and predicts poor prognosis in patients with cancer (29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

HPIP is an essential scaffolding protein running through the EGFR-RAS-ERK pathway and drives tumorigenesis

Jiang,

Zhang,

Liu

et al. 2023

Sci. Adv.

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The EGFR-RAS-ERK pathway plays a key role in cancer development and progression. However, the integral assembly of EGFR-RAS-ERK signaling complexes from the upstream component EGFR to the downstream component ERK is largely unknown. Here, we show that hematopoietic PBX-interacting protein (HPIP) interacts with all classical components of the EGFR-RAS-ERK pathway and forms at least two complexes with overlapping components. Experiments of HPIP knockout or knockdown and chemical inhibition of HPIP expression showed that HPIP is required for EGFR-RAS-ERK signaling complex formation, EGFR-RAS-ERK signaling activation, and EGFR-RAS-ERK signaling–mediated promotion of aerobic glycolysis as well as cancer cell growth in vitro and in vivo. HPIP expression is correlated with EGFR-RAS-ERK signaling activation and predicts worse clinical outcomes in patients with lung cancer. These results provide insights into EGFR-RAS-ERK signaling complex formation and EGFR-RAS-ERK signaling regulation and suggest that HPIP may be a promising therapeutic target for cancer with dysregulated EGFR-RAS-ERK signaling.

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“…Numerous studies have shown that HPIP is highly expressed in many cancers like gastric cancer, colorectal cancer, hepatocellular carcinoma (HCC), glioma, leiomyosarcomas, oral carcinoma, and ovarian cancer [11,[14][15][16][17][18]. In case of breast cancer, it interacts with microtubules and negatively regulates transcriptional activity of estrogen receptor alpha (ERa) [17,19]. All the accumulating evidence support that HPIP promotes cell proliferation, migration, anchorage-independent growth, and invasion of cancer cells through the activation of AKT/MAPK pathways [14,17,20].…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic PBX‐interacting protein is a novel regulator of mammary epithelial cell differentiation

et al. 2021

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Hematopoietic PBX‐interacting protein (HPIP, also known as PBXIP1) is an estrogen receptor (ER) interacting protein that regulates estrogen‐mediated breast cancer cell proliferation and tumorigenesis. However, its functional significance in the context of mammary gland development is unexplored. Here, we report that HPIP is required for prolactin (PRL)‐induced lactogenic differentiation in vitro. Molecular analysis of HPIP expression in mice revealed its induced expression at pregnancy and lactation stages of mammary gland. Moreover, PRL is a lactogenic hormone that controls pregnancy as well as lactation and induces Hpip/Pbxip1 expression in a signal transducer and activator of transcription 5a‐dependent manner. Using mammary epithelial and lactogenic‐competent cell lines, we further show that HPIP plays a regulatory role in PRL‐mediated mammary epithelial cell differentiation, which is measured by acini formation, β‐casein synthesis, and lipid droplet formation. Further mechanistic studies using pharmacological inhibitors revealed that HPIP modulates PRL‐induced β‐casein synthesis via phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) activation. This study also identified HPIP as a critical regulator of autocrine PRL signaling as treatment with the PRL receptor antagonist Δ1‐9‐G129R‐hPRL restrained HPIP‐mediated PRL synthesis, AKT activation, and β‐casein synthesis in cultured HC11 cells. Interestingly, we also uncovered that microRNA‐148a (miR‐148a) antagonizes HPIP‐mediated mammary epithelial cell differentiation. Together, our study identified HPIP as a critical regulator of PRL signaling and revealed a novel molecular circuitry involving PRL, HPIP, PI3K/AKT, and miR‐148a that controls mammary epithelial cell differentiation in vitro.

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Two decades of a protooncogene HPIP/PBXIP1: Uncovering the tale from germ cell to cancer

Cited by 18 publications

References 71 publications

Prdm16mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators

Prdm16mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators

HPIP is an essential scaffolding protein running through the EGFR-RAS-ERK pathway and drives tumorigenesis

Hematopoietic PBX‐interacting protein is a novel regulator of mammary epithelial cell differentiation

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