Philipp Kaldis

Philipp Kaldis
Lund University | LU · Department of Clinical Sciences, Malmö

PhD

About

195
Publications
37,406
Reads
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10,109
Citations
Citations since 2017
56 Research Items
4481 Citations
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20172018201920202021202220230200400600800
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Introduction
I work on kinases, the most easily druggable class of enzymes. We use genetically modified mouse models with loss or gain of function models for cyclin-dependent kinases (Cdk). Lately, we have focused on liver regeneration and cancer, where we study how cell division is coordinated with metabolism. I am an expert in kinase activation, how kinases regulate their substrates and downstream biological processes, how the liver regenerates, and in target validation for cancer and metabolic diseases.
Additional affiliations
September 2019 - present
Lund University
Position
  • Professor
August 2007 - August 2019
Institute of Molecular and Cell Biology (IMCB)
Position
  • Genetic mouse models to study cell cycle, cancer, and meiosis
August 2000 - August 2007
NCI-Frederick
Position
  • Cdk knockout mice
Education
November 1990 - April 1994
ETH Zurich
Field of study
  • Biochemistry / mitochondrial creatine kinase
August 1986 - June 1990
ETH Zurich
Field of study
  • Biochemistry

Publications

Publications (195)
Article
Full-text available
The PRDM family of methyltransferases has been implicated in cellular proliferation and differentiation and is deregulated in human diseases, most notably in cancer. PRDMs are related to the SET domain family of methyltransferases; however, from the 19 PRDMs only a few PRDMs with defined enzymatic activities are known. PRDM15 is an uncharacterized...
Article
Full-text available
Excessive fat accumulation in the liver has become a major health threat worldwide. Unresolved fat deposition in the liver can go undetected until it develops into fatty liver disease, followed by steatohepatitis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Lipid deposition in the liver is governed by complex communication, primar...
Article
Full-text available
Methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a new drug target that is expressed in cancer cells but not in normal adult cells, which provides an Achilles heel to selectively kill cancer cells. Despite the availability of crystal structures of MTHFD2 in the inhibitor- and cofactor-bound forms, key information is missing due to...
Article
Mammalian metabolism comprises a series of interlinking pathways that include two major cycles: the folate and methionine cycles. The folate‐mediated metabolic cycle uses several oxidation states of tetrahydrofolate to carry activated one‐carbon units to be readily used and interconverted within the cell, which are required for nucleotide synthesis...
Article
Full-text available
Diabetes is a complex and multifactorial disease that affects millions of people worldwide, reducing the quality of life significantly, and results in grave consequences for our health care system. In Type 2 Diabetes (T2D), the lack of β‐cell compensatory mechanisms overcoming peripherally developed insulin resistance is a paramount factor leading...
Preprint
Full-text available
Methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a new drug target that is expressed in cancer cells but not in normal adult cells, which provides an Achilles heel to selectively kill cancer cells. Despite the availability of crystal structures of MTHFD2 in the inhibitor- and cofactor-bound forms, key information is missing due to...
Article
Full-text available
Lignin is one of the world's most abundant organic polymers, and 2-pyrone-4,6-dicarboxylate lactonase (LigI) catalyzes the hydrolysis of 2-pyrone-4,6-dicarboxylate (PDC) in the degradation of lignin. The pH has profound effects on enzyme catalysis and therefore we studied this in the context of LigI. We found that changes of the pH mostly affects s...
Preprint
Lignin is one of the world’s most abundant organic polymers, and 2-pyrone-4,6-dicarboxylate lactonase (LigI) catalyzes the hydrolysis of 2-pyrone-4,6-dicarboxylate (PDC) in the degradation of lignin. The pH has profound effects on enzyme catalysis and therefore we studied this in the context of LigI. We found that changes of the pH mostly affects s...
Article
Most of the drugs currently prescribed for cancer treatment are riddled with substantial side effects. In order to develop more effective and specific strategies to treat cancer, it is of importance to understand the biology of drug targets, particularly the newly emerging ones. A comprehensive evaluation of these targets will benefit drug developm...
Article
Full-text available
BACKGROUND & AIMS Liver tight junctions (TJs) establish tissue barriers that isolate bile from the blood circulation. TJP2/ZO-2-inactivating mutations cause progressive cholestatic liver disease in humans. Since the underlying mechanisms remain elusive, we characterized mice with liver-specific inactivation of Tjp2. METHODS Tjp2 was deleted in hep...
Article
Full-text available
Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid metabolism and the consequent impact on whole-body physiology...
Article
Full-text available
The liver possesses a remarkable regenerative capacity based partly on the ability of hepatocytes to re-enter the cell cycle and divide to replace damaged cells. This capability is substantially reduced upon chronic damage, but it is not clear if this is a cause or consequence of liver disease. Here, we investigate whether blocking hepatocyte divis...
Article
Full-text available
Progression through mitosis is balanced by the timely regulation of phosphorylation and dephosphorylation events ensuring the correct segregation of chromosomes before cytokinesis. This balance is regulated by the opposing actions of CDK1 and PP2A, as well as the Greatwall kinase/MASTL. MASTL is commonly overexpressed in cancer, which makes it a po...
Article
Full-text available
Genetic diversity in offspring is induced by meiotic recombination, which is initiated between homologs at >200 sites originating from meiotic double-strand breaks (DSBs). Of this initial pool, only 1–2 DSBs per homolog pair will be designated to form meiotic crossovers (COs), where reciprocal genetic exchange occurs between parental chromosomes. C...
Article
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Satellite cell proliferation is an essential step in proper skeletal muscle development and muscle regeneration. However, the mechanisms regulating satellite cell proliferation are relatively unknown compared to the knowledge associated with the differentiation of satellite cells. Moreover, it is still unclear whether overload muscle fiber hypertro...
Article
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SUGCT (C7orf10) is a mitochondrial enzyme that synthesizes glutaryl-CoA from glutarate in tryptophan and lysine catabolism, but it has not been studied in vivo. Although mutations in Sugct lead to Glutaric Aciduria Type 3 disease in humans, patients remain largely asymptomatic despite high levels of glutarate in the urine. To study the disease mech...
Article
Full-text available
PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. Despite its well character...
Article
Full-text available
Cell division is essential for organismal growth and tissue homeostasis. It is exceptionally significant in tissues chronically exposed to intrinsic and external damage, like the liver. After decades of studying the regulation of cell cycle by extracellular signals, there are still gaps in our knowledge on how these two interact with metabolic path...
Article
Full-text available
We have developed MetaboKit, a comprehensive software package for compound identification and relative quantification in mass spectrometry-based untargeted metabolomics analysis. In data dependent acquisition (DDA) analysis, MetaboKit constructs a customized spectral library with compound identities from reference spectral libraries, adducts, dimer...
Chapter
Full-text available
Cyclin-dependent kinases (CDKs) are activated by cyclins, which play important roles in dictating the actions of CDK/cyclin complexes. Cyclin binding influences the substrate specificity of these complexes in addition to their susceptibility to inhibition or degradation. CDK/cyclin complexes are best known to promote cell cycle progression in the m...
Article
Full-text available
Cyclin-dependent kinases (CDKs) are activated by cyclins, which play important roles in dictating the actions of CDK/cyclin complexes. Cyclin binding influences the substrate specificity of these complexes in addition to their susceptibility to inhibition or degradation. CDK/cyclin complexes are best known to promote cell cycle progression in the m...
Article
Full-text available
Spermatogenesis relies on exquisite stem cell homeostasis, the carefully balanced self-renewal and differentiation of spermatogonial stem cells (SSCs). Disturbing this equilibrium will likely manifest through sub- or infertility, a global health issue with often idiopathic presentation. In this respect, disease phenotypes caused by haploinsufficien...
Article
Full-text available
The S‐adenosyl‐L‐methionine (SAM)‐dependent methyltransferases attach a methyl group to the deprotonated methyl lysine (Kme0) using SAM as a donor. An intriguing, yet unanswered, question is how the deprotonation of the methyl lysine takes place which results in a lone pair of electrons at the Nϵ atom of the methyl lysine for the following methyl t...
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
A hallmark of polycystic kidney diseases (PKDs) is aberrant proliferation, which leads to the formation and growth of renal cysts. Proliferation is mediated by cyclin-dependent kinases (Cdks), and the administration of roscovitine (a pan-Cdk inhibitor) attenuates renal cystic disease in juvenile cystic kidney (jck) mice. Cdk2 is a key regulator of...
Article
Full-text available
PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant e...
Preprint
BACKGROUND & AIMS Tight junctions (TJs) establish tissue barriers that maintain osmotic homeostasis and, in the liver, isolate bile flow from the blood circulation. ZO-2/Tjp2 is a scaffold protein that tethers TJ transmembrane proteins to the actin cytoskeleton. Missense mutations in Tjp2 have recently been shown to cause progressive cholestatic li...
Article
The ability of men to remain fertile throughout their lives depends upon establishment of a spermatogonial stem cell (SSC) pool from gonocyte progenitors, and thereafter balancing SSC renewal vs terminal differentiation. Here, we report that precise regulation of the cell cycle is crucial for this balance. Whereas cyclin-dependent kinase 2 (Cdk2) i...
Article
Full-text available
Meiosis generates four genetically distinct haploid gametes over the course of two reductional cell divisions. Meiotic divisions are characterized by the coordinated deposition and removal of various epigenetic marks. Here we propose that nuclear respiratory factor 1 (NRF1) regulates transcription of euchromatic histone methyltransferase 1 (EHMT1)...
Article
Full-text available
The primary function of cyclin‐dependent kinases (CDKs) in complex with their activating cyclin partners, is to promote mitotic division in somatic cells. This canonical cell cycle‐associated activity is also crucial for fertility as it allows the proliferation and differentiation of stem cells within the reproductive organs to generate meiotically...
Article
Full-text available
Interleukin (IL)-1-family cytokines potently regulate inflammation, with the majority of the IL-1 family proteins being secreted from immune cells via unconventional pathways. In many cases, secretion of IL-1 cytokines appears to be closely coupled to cell death, yet the secretory mechanisms involved remain poorly understood. Here, we studied the s...
Preprint
The ability of men to remain fertile throughout their lives depends upon establishment of a spermatogonial stem cell (SSC) pool from gonocyte progenitors, and also maintaining the proper balance between SSC renewal and spermatogenic differentiation throughout life. Depletion of SSCs causes infertility with a Sertoli Cell Only Syndrome (SCOS) phenot...
Article
Full-text available
Cell cycle regulation, especially faithful DNA replication and mitosis, are crucial to maintain genome stability. Cyclin-dependent kinase (CDK)/cyclin complexes drive most processes in cellular proliferation. In response to DNA damage, cell cycle surveillance mechanisms enable normal cells to arrest and undergo repair processes. Perturbations in ge...
Article
Full-text available
Bone mass is maintained by a balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Although recent genetic studies have uncovered various mechanisms that regulate osteoblast differentiation, the molecular basis of osteoblast proliferation remains unclear. Here, using an osteoblast-specific loss-of-function mous...
Article
Liver disease is linked to a decreased capacity of hepatocytes to divide. In addition, cellular metabolism is important for tissue homeostasis and regeneration. Since metabolic changes are a hallmark of liver disease, we investigated the connections between metabolism and cell division. We determined global metabolic changes at different stages of...
Article
Global profiling of protein expression through the cell cycle has revealed subsets of periodically expressed proteins. However, expression levels alone only give a partial view of processes determining cellular events. The cell cycle progression events are to a large extent controlled by the dynamic biochemical interactions of proteins with physiol...
Cover Page
Full-text available
Join the Kaldis lab as a postdoctoral fellow: Metabolic remodeling during liver regeneration & disease
Article
Global profiling of protein expression through the cell cycle has revealed subsets of periodically expressed proteins. However, expression levels alone only give a partial view of the biochemical processes determining cellular events. Using a proteome-wide implementation of the cellular thermal shift assay (CETSA) to study specific cell-cycle phase...
Article
Full-text available
Cell cycle proteins are mainly expressed by dividing cells. However, it is well established that these molecules play additional non-canonical activities in several cell death contexts. Increasing evidence shows expression of cell cycle regulating proteins in post-mitotic cells, including mature neurons, following neuronal insult. Several cyclin-de...
Article
Taking the heat together Many of the processes in living cells are mediated by protein complexes that dynamically assemble and dissociate depending on cellular needs. Tan et al. developed a method called thermal proximity coaggregation (TPCA) to monitor the dynamics of native protein complexes inside cells (see the Perspective by Li et al. ). The m...
Article
Full-text available
Telomeres integrity is indispensable for chromosomal stability by preventing chromosome erosion and end-to-end fusions. During meiosis, telomeres attach to the inner nuclear envelope and cluster into a highly crowded microenvironment at the bouquet stage, which requires specific mechanisms to protect the telomeres from fusion. Here, we demonstrate...
Article
In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation , spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this...
Article
The maintenance of cell size homeostasis has been studied for years in different cellular systems. With the focus on 'what regulates cell size', the question 'why cell size needs to be maintained' has been largely overlooked. Recent evidence indicates that animal cells exhibit nonlinear cell size dependent growth rates and mitochondrial metabolism,...
Article
Full-text available
The meiotic functions of Emi2, an inhibitor of the APC/C complex, have been best characterized in oocytes where it mediates metaphase II arrest as a component of the cytostatic factor. We generated knockout mice to determine the in vivo functions of Emi2—in particular, its functions in the testis, where Emi2 is expressed at high levels. Male and fe...
Article
Sox2 is known to be important for neuron formation but the precise mechanism through which it activates a neurogenic program and how this differs from its well-established function in self-renewal remain elusive. Here, we identify a highly conserved Cdk phosphorylation site on serine 39 (S39) in Sox2. In neural stem cells (NSCs), phosphorylation of...
Article
Full-text available
The failure of pancreatic islet β-cells is a major contributor to the etiology of Type 2 diabetes. β-cell dysfunction and declining β-cell mass are two mechanisms that contribute to this failure, although it is unclear if they are molecularly linked. Here, we show that the cell cycle regulator, cyclin-dependent kinase 2 (Cdk2), couples primary β-ce...
Article
Full-text available
In mammals, primordial germ cells (PGCs) are the embryonic cell population that serve as germ cell precursors in both females and males. During mouse embryonic development, the majority of PGCs are arrested at the G2 phase when they migrate into the hindgut at 7.75-8.75 dpc (days post coitum). It is after 9.5 dpc that the PGCs undergo proliferation...
Article
Full-text available
Significance In meiotic prophase I, telomere attachment to the nuclear envelope is a prerequisite for subsequent prophase events, such as homologous pairing and recombination. In this study, we show that Speedy A, a noncanonical activator of cyclin-dependent kinases (Cdks), is essential for telomere attachment to the nuclear envelope in mice. We ha...
Article
The cohesin ring, which is composed of the Smc1, Smc3, and Scc1 subunits, topologically embraces two sister chromatids from S phase until anaphase to ensure their precise segregation to the daughter cells. The opening of the ring is required for its loading on the chromosomes and unloading by the action of Wpl1 protein. Both loading and unloading a...
Data
Schematic diagram of oocyte development in Cdk1+/SAF, OoCdk1+/AF; Gdf9-Cre and OoCdk1+/AF; Zp3-Cre mouse ovaries.
Data
Comparison of ovarian morphology and quantification of ovarian follicles.
Data
Increased ATM activation in GV stage OoCdk1+/AF; Zp3-Cre oocytes and quantification of ovarian follicles in OoCdk1+/AF; Zp3-Cre; Chk2−/− mice.
Article
Full-text available
A unique feature of female germ cell development in mammals is their remarkably long arrest at the prophase of meiosis I, which lasts up to 50 years in humans. Both dormant and growing oocytes are arrested at prophase I and completely lack the ability to resume meiosis. Here, we show that the prolonged meiotic arrest of female germ cells is largely...
Article
Full-text available
Cyclin A2 is an essential gene for development and in hematopoietic stem cells and therefore its functions in definitive erythropoiesis have not been investigated. We have ablated cyclin A2 in committed erythroid progenitors in vivo using erythropoietin receptor promoter-driven Cre, which revealed its critical role in regulating erythrocyte morphol...
Article
Full-text available
The Greatwall kinase/Mastl is an essential gene that indirectly inhibits the phosphatase activity toward mitotic Cdk1 substrates. Here we show that although Mastl knockout (MastlNULL) MEFs enter mitosis, they progress through mitosis without completing cytokinesis despite the presence of misaligned chromosomes, which causes chromosome segregation d...
Data
Localization of phosphorylated MPS1 on T675 and T685 in early mitosis. (A) Primary MastlFLOX and MastlNULL MEFs were treated as in Fig 4 to arrest in mitosis and were fixed. Immunofluorescence analysis was performed using ACA and antibodies against MPS1-pST685 or -pS820. Early mitotic phase was determined with cells containing lightly condensed chr...
Data
Primers used in this study. (PDF)
Data
Complete phospho-proteomic mass spectrometry data. (XLSX)