A role of intracellular mono-ADP-ribosylation in cancer biology

Reactive intermediate deaminase (Rid) proteins are enzymes conserved in all domains of life. UK114, a mammalian member of RidA subfamily, has been firstly identified as a component of liver perchloric acid-soluble proteins (L-PSP). Although still poorly defined, several functions have been attributed to the mammalian protein UK114/RIDA, including the reactive intermediate deamination activity. The expression of UK114/RIDA has been observed in some tumors, arousing interest in this protein as an evaluable tumor marker. However, other studies reported a negative correlation between UK114/RIDA expression, tumor differentiation degree and cell proliferation. This work addressed the question of UK114/RIDA expression in human non-tumor HEK293 cell lines and in some human tumor cell lines. Here we reported that human RIDA (hRIDA) was expressed in all the analyzed cell line and subjected to lysine (K-)succinylation. In HEK293, hRIDA K-succinylation was negatively correlated to the cell proliferation rate and was under the control of SIRT5. Moreover, K-succinylation clearly altered hRIDA quantification by immunoblotting, explaining, at least in part, some discrepancies about RIDA expression reported in previous studies. We found that hRIDA was able to deaminate reactive enamine-imine intermediates and that K-succinylation drastically reduced deaminase activity. As predicted by in silico analysis, the observed reduction of deaminase activity has been related to the drastic alterations of hRIDA structure inferred by K-succinylation. The role of hRIDA and the importance of its K-succinylation in cell metabolism, especially in cancer biology, have been discussed.

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Role of long interspersed nuclear element-1 in the regulation of chromatin landscapes and genome dynamics

Experimental Biology and Medicine ◽

10.1177/15353702211031247 ◽

2021 ◽

pp. 153537022110312

Author(s):

Kenneth S Ramos ◽

Pasano Bojang ◽

Emma Bowers

Keyword(s):

Cancer Biology ◽

Mobile Element ◽

Cancer Diagnostics ◽

Regulatory Control ◽

Full Potential ◽

Genome Dynamics ◽

Human Illness ◽

Cancer Types ◽

Stressful Environments

LINE-1 retrotransposon, the most active mobile element of the human genome, is subject to tight regulatory control. Stressful environments and disease modify the recruitment of regulatory proteins leading to unregulated activation of LINE-1. The activation of LINE-1 influences genome dynamics through altered chromatin landscapes, insertion mutations, deletions, and modulation of cellular plasticity. To date, LINE-1 retrotransposition has been linked to various cancer types and may in fact underwrite the genetic basis of various other forms of chronic human illness. The occurrence of LINE-1 polymorphisms in the human population may define inter-individual differences in susceptibility to disease. This review is written in honor of Dr Peter Stambrook, a friend and colleague who carried out highly impactful cancer research over many years of professional practice. Dr Stambrook devoted considerable energy to helping others live up to their full potential and to navigate the complexities of professional life. He was an inspirational leader, a strong advocate, a kind mentor, a vocal supporter and cheerleader, and yes, a hard critic and tough friend when needed. His passionate stand on issues, his witty sense of humor, and his love for humanity have left a huge mark in our lives. We hope that that the knowledge summarized here will advance our understanding of the role of LINE-1 in cancer biology and expedite the development of innovative cancer diagnostics and treatments in the ways that Dr Stambrook himself had so passionately envisioned.

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Identification of circRNA circ-CSPP1 as a potent driver of colorectal cancer by directly targeting the miR-431/LASP1 axis

Open Life Sciences ◽

10.1515/biol-2021-0053 ◽

2021 ◽

Vol 16 (1) ◽

pp. 523-536

Author(s):

Minghao Li ◽

Jianbin Zhuang ◽

Di Kang ◽

Yuzhuo Chen ◽

Weiliang Song

Keyword(s):

Colorectal Cancer ◽

Cancer Biology ◽

Spindle Pole ◽

Circular Rnas ◽

Cell Progression ◽

Crc Management ◽

Common Malignancy

Abstract Colorectal cancer (CRC) is the third most common malignancy worldwide. Circular RNAs (circRNAs) have been implicated in cancer biology. The purpose of the current work is to investigate the precise parts of circRNA centrosome and spindle pole-associated protein 1 (circ-CSPP1) in the progression of CRC. Our data showed that circ-CSPP1 was significantly overexpressed in CRC tissues and cells. The knockdown of circ-CSPP1 attenuated cell proliferation, migration, invasion and promoted apoptosis in vitro and weakened tumor growth in vivo. circ-CSPP1 directly targeted miR-431, and circ-CSPP1 knockdown modulated CRC cell progression in vitro via upregulating miR-431. Moreover, LIM and SH3 protein 1 (LASP1) was a functional target of miR-431 in modulating CRC cell malignant progression. Furthermore, circ-CSPP1 in CRC cells functioned as a posttranscriptional regulator on LASP1 expression by targeting miR-431. Our present study identified the oncogenic role of circ-CSPP1 in CRC partially by the modulation of the miR-431/LASP1 axis, providing evidence for circ-CSPP1 as a promising biomarker for CRC management.

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Effect of acidosis on PTH-dependent renal adenylate cyclase in phosphorus deprivation: role of G proteins

AJP Renal Physiology ◽

10.1152/ajprenal.1990.258.6.f1640 ◽

1990 ◽

Vol 258 (6) ◽

pp. F1640-F1649

Author(s):

E. Bellorin-Font ◽

R. Starosta ◽

C. L. Milanes ◽

C. Lopez ◽

N. Pernalete ◽

...

Keyword(s):

Metabolic Acidosis ◽

Adenylate Cyclase ◽

Maximal Activity ◽

Phosphate Deprivation ◽

Adp Ribosylation ◽

Phosphate Depletion ◽

Cortical Membranes ◽

And Function ◽

Gs Alpha

These studies examine the regulation of adenylate cyclase in renal cortical membranes from phosphate-deprived and phosphate-deprived acidotic dogs. Enzyme stimulation by parathyroid hormone (PTH) was decreased in phosphate deprivation [Vmax 1,578 +/- 169 vs. 2,581 +/- 219 pmol adenosine 3',5'-cyclic monophosphate (cAMP).mg protein-1 x 30 min-1 in controls, P less than 0.01]. Metabolic acidosis further decreased PTH-stimulated activity. Membranes from phosphate-deprived dogs showed a decrease in Gs alpha-content by cholera toxin-dependent ADP-ribosylation (174 +/- 18 arbitrary units vs. 266.4 +/- 13.6 in controls, P less than 0.01). Metabolic acidosis further decreased Gs alpha-content, P less than 0.01. Gi content by pertussis-dependent ADP-ribosylation was also lower in phosphate-deprived and phosphate-deprived acidotic animals. Gs function was examined by its property to protect the catalytic unit from inactivation by N-ethylmaleimide when preincubated with GTP gamma S. In controls, protection of inactivation was 80% of the maximal activity, whereas in phosphate deprivation protection was less than 50%. In conclusion, metabolic acidosis enhances adenylate cyclase resistance to PTH in phosphate deprivation. These alterations are associated with a decrease in the content and function of Gs alpha, suggesting a role of Gs in the renal adaptation to phosphate depletion and acidosis.

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NO-Donating NSAIDs, PPARδ, and Cancer: Does PPARδContribute to Colon Carcinogenesis?

PPAR Research ◽

10.1155/2008/919572 ◽

2008 ◽

Vol 2008 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Gerardo G. Mackenzie ◽

Shaheen Rasheed ◽

William Wertheim ◽

Basil Rigas

Keyword(s):

Cancer Biology ◽

Antitumor Effect ◽

Colon Carcinogenesis ◽

Wild Type ◽

Antineoplastic Effect ◽

Intestinal Neoplasia ◽

Chemopreventive Effect ◽

The Relationship ◽

Epithelial Cell Death

The chemopreventive NO-donating NSAIDs (NO-NSAIDs; NSAIDs with an NO-releasing moiety) modulate PPARδand offer the opportunity to revisit the controversial role of PPARδin carcinogenesis (several papers report that PPARδeither promotes or inhibits cancer). This review summarizes the pharmacology of NO-NSAIDs, PPARδcancer biology, and the relationship between the two. In particular, a study of the chemopreventive effect of two isomers of NO-aspirin on intestinal neoplasia inMinmice showed that, compared to wild-type controls, PPARδis overexpressed in the intestinal mucosa ofMinmice; PPARδresponds tom- andp-NO-ASA proportionally to their antitumor effect (p->m-). This effect is accompanied by the induction of epithelial cell death, which correlates with the antineoplastic effect of NO-aspirin; and NO-aspirin's effect on PPARδis specific (no changes in PPARαor PPARγ). Although these data support the notion that PPARδpromotes intestinal carcinogenesis and its inhibition could be therapeutically useful, more work is needed before a firm conclusion is reached.

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Active-Site Mutations of the Diphtheria Toxin Catalytic Domain: Role of Histidine-21 in Nicotinamide Adenine Dinucleotide Binding and ADP-Ribosylation of Elongation Factor 2

Biochemistry ◽

10.1021/bi00183a019 ◽

1994 ◽

Vol 33 (17) ◽

pp. 5155-5161 ◽

Cited By ~ 43

Author(s):

Steven R. Blanke ◽

Kathy Huang ◽

Brenda A. Wilson ◽

Emanuele Papini ◽

Antonello Covacci ◽

...

Keyword(s):

Active Site ◽

Nicotinamide Adenine Dinucleotide ◽

Diphtheria Toxin ◽

Catalytic Domain ◽

Elongation Factor ◽

Nicotinamide Adenine ◽

Adp Ribosylation ◽

Elongation Factor 2 ◽

Active Site Mutations

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The role of hyaluronan in pancreatic cancer biology and therapy

Pancreatology ◽

10.1016/j.pan.2016.06.612 ◽

2016 ◽

Vol 16 (4) ◽

pp. S170

Author(s):

Norihiro Sato ◽

Shiro Kohi ◽

Atsuhiro Koga ◽

Keiji Hirata

Keyword(s):

Pancreatic Cancer ◽

Cancer Biology

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Role of the N-terminal region in covalent modification of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: comparison of phosphorylation and ADP-ribosylation

Biochemical Journal ◽

10.1042/bj3090119 ◽

1995 ◽

Vol 309 (1) ◽

pp. 119-125 ◽

Cited By ~ 4

Author(s):

J L Rosa ◽

J X Pérez ◽

F Ventura ◽

A Tauler ◽

J Gil ◽

...

Keyword(s):

Protein Kinase ◽

Covalent Modification ◽

Terminal Region ◽

Bifunctional Enzyme ◽

Dependent Protein Kinase ◽

Adp Ribosylation ◽

Camp Dependent Protein Kinase ◽

Arginine Residues ◽

Dependent Protein

The effect of cyclic AMP (cAMP)-dependent phosphorylation and ADP-ribosylation on the activities of the rat liver bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2), was investigated in order to determine the role of the N-terminus in covalent modification of the enzyme. The bifunctional enzyme was demonstrated to be a substrate in vitro for arginine-specific ADP-ribosyltransferase: 2 mol of ADP-ribose was incorporated per mol of subunit. The Km values for NAD+ and PFK-2/FBPase-2 were 14 microM and 0.4 microM respectively. A synthetic peptide (Val-Leu-Gln-Arg-Arg-Arg-Gly-Ser-Ser-Ile-Pro-Gln) corresponding to the site phosphorylated by cAMP-dependent protein kinase was ADP-ribosylated on all three arginine residues. Analysis of ADP-ribosylation of analogue peptides containing only two arginine residues, with the third replaced by alanine, revealed that ADP-ribosylation occurred predominantly on the two most C-terminal arginine residues. Sequencing of the ADP-ribosylated native enzyme also demonstrated that the preferred sites were at Arg-29 and Arg-30, which are just N-terminal to Ser-32, whose phosphorylation is catalysed by cAMP-dependent protein kinase (PKA). ADP-ribosylation was independent of the phosphorylation state of the enzyme. Furthermore, ADP-ribosylation of the enzyme decreased its recognition by liver-specific anti-bifunctional-enzyme antibodies directed to its unique N-terminal region. ADP-ribosylation of PFK-2/FBPase-2 blocked its phosphorylation by PKA, and decreased its PFK-2 activity, but did not alter FBPase-2 activity. In contrast, cAMP-dependent phosphorylation inhibited the kinase and activated the bisphosphatase. These results demonstrate that ADP-ribosylation of arginine residues just N-terminal to the site phosphorylated by PKA modulate PFK-2 activity by an electrostatic and/or steric mechanism which does not involved uncoupling of N- and C-terminal interactions as seen with cAMP-dependent phosphorylation.

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Polypeptide-GalNAc-Transferase-13 Shows Prognostic Impact in Breast Cancer

Cancers ◽

10.3390/cancers13225616 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5616

Author(s):

Eugenia Fernandez ◽

Luis Ubillos ◽

Nabila Elgul ◽

María Florencia Festari ◽

Daniel Mazal ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Nodes ◽

Cancer Biology ◽

Molecular Mechanisms ◽

Health Concern ◽

Breast Cancer Cell Lines ◽

Prognostic Impact ◽

Metastatic Lymph Nodes ◽

Metastatic Lymph

Breast cancer is a public health concern and is currently the fifth cause of mortality worldwide. Identification of different biological subtypes is essential for clinical management; therefore, the role of pathologists is essential and useful tools for immunohistochemistry diagnosis are needed. Polypeptide-GalNAc-transferases are emerging novel biomarkers related to cancer behavior and GalNAc-T13, correlated with aggressiveness in some tumors, is an interesting candidate. Few monoclonal antibodies reacting with native proteins, and not affected by fixation and paraffin embedding, have been reported. The aim of this work was to develop a useful monoclonal antibody anti-GalNAc-T13 and to assess its potential significance in breast cancer diagnosis. We evaluated 6 human breast cancer cell lines, 338 primary breast tumors and 48 metastatic lymph nodes and looked for clinical significance correlating GalNAc-T13 expression with patients’ clinical features and survival. We found high GalNAc-T13 expression in 43.8% of the cases and observed a significant higher expression in metastatic lymph nodes, correlating with worse overall survival. We hypothesized several possible molecular mechanisms and their implications. We conclude that GalNAc-T13 may be a novel biomarker in breast cancer, useful for routine pathological diagnosis. Elucidation of molecular mechanisms related to aggressiveness should contribute to understand the role of GalNAc-T13 in breast cancer biology.

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