scholarly journals A PAS Protein Directs Metabolic Reprogramming during Cryptococcal Adaptation to Hypoxia

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Youbao Zhao ◽  
Xiaorong Lin
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Metabolic Response ◽  
Regulatory Element ◽  
Metabolic Reprogramming ◽  
Adaptation To Hypoxia ◽  
Content Type ◽  
Hypoxic Adaptation ◽  
Lower Eukaryotes ◽  
Hypoxia Adaptation

ABSTRACT To aerobic organisms, low oxygen tension (hypoxia) presents a physiological challenge. To cope with such a challenge, metabolic pathways such as those used in energy production have to be adjusted. Many of such metabolic changes are orchestrated by the conserved hypoxia-inducible factors (HIFs) in higher eukaryotes. However, there are no HIF homologs in fungi or protists, and not much is known about conductors that direct hypoxic adaptation in lower eukaryotes. Here, we discovered that the transcription factor Pas2 controls the transcript levels of metabolic genes and consequently rewires metabolism for hypoxia adaptation in the human fungal pathogen Cryptococcus neoformans. Through genetic, proteomic, and biochemical analyses, we demonstrated that Pas2 directly interacts with another transcription factor, Rds2, in regulating cryptococcal hypoxic adaptation. The Pas2/Rds2 complex represents the key transcription regulator of metabolic flexibility. Its regulation of metabolism rewiring between respiration and fermentation is critical to our understanding of the cryptococcal response to low levels of oxygen. IMPORTANCE C. neoformans is the main causative agent of fungal meningitis that is responsible for about 15% of all HIV-related deaths. Although an obligate aerobic fungus, C. neoformans is well adapted to hypoxia conditions that the fungus could encounter in the host or the environment. The sterol regulatory element binding protein (SREBP) is well known for its role in cryptococcal adaptation to hypoxia through its regulation of ergosterol and lipid biosynthesis. The regulation of metabolic reprogramming under hypoxia, however, is largely unknown. Here, we discovered one key regulator, Pas2, that mediates the metabolic response to hypoxia together with another transcription factor, Rds2, in C. neoformans. The findings help define the molecular mechanisms underpinning hypoxia adaptation in this and other lower eukaryotes.

scholarly journals The Putative APSES Transcription Factor RgdA Governs Growth, Development, Toxigenesis, and Virulence in Aspergillus fumigatus

mSphere ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
Sang-Cheol Jun ◽  
Yong-Ho Choi ◽  
Min-Woo Lee ◽  
Jae-Hyuk Yu ◽  
Kwang-Soo Shin
Keyword(s):  
Transcription Factor ◽  
Aspergillus Fumigatus ◽  
Molecular Mechanisms ◽  
Pathogenic Fungus ◽  
Mrna Levels ◽  
Transcript Levels ◽  
Content Type ◽  
Asexual Sporulation ◽  
Human Pathogenic Fungus ◽  
Growth Development

ABSTRACT The APSES transcription factor (TF) in Aspergillus species is known to govern diverse cellular processes, including growth, development, and secondary metabolism. Here, we investigated functions of the rgdA gene (Afu3g13920) encoding a putative APSES TF in the opportunistic human-pathogenic fungus Aspergillus fumigatus. The rgdA deletion resulted in significantly decreased hyphal growth and asexual sporulation. Consistently, transcript levels of the key asexual developmental regulators abaA, brlA, and wetA were decreased in the ΔrgdA mutant compared to those in the wild type (WT). Moreover, ΔrgdA resulted in reduced spore germination rates and elevated transcript levels of genes associated with conidium dormancy. The conidial cell wall hydrophobicity and architecture were changed, and levels of the RodA protein were decreased in the ΔrgdA mutant. Comparative transcriptomic analyses revealed that the ΔrgdA mutant showed higher mRNA levels of gliotoxin (GT)-biosynthetic genes and GT production. While the ΔrgdA mutant exhibited elevated production of GT, ΔrgdA strains showed reduced virulence in the mouse model. In addition, mRNA levels of genes associated with the cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway and the SakA mitogen-activated protein (MAP) kinase pathway were increased in the ΔrgdA mutant. In summary, RgdA plays multiple roles in governing growth, development, GT production, and virulence which may involve attenuation of PKA and SakA signaling. IMPORTANCE Immunocompromised patients are susceptible to infections with the opportunistic human-pathogenic fungus Aspergillus fumigatus. This fungus causes systemic infections such as invasive aspergillosis (IA), which is one of the most life-threatening fungal diseases. To control this serious disease, it is critical to identify new antifungal drug targets. In fungi, the transcriptional regulatory proteins of the APSES family play crucial roles in controlling various biological processes, including mating, asexual sporulation and dimorphic growth, and virulence traits. This study found that a putative APSES transcription factor, RgdA, regulates normal growth, asexual development, conidium germination, spore wall architecture and hydrophobicity, toxin production, and virulence in A. fumigatus. Better understanding the molecular mechanisms of RgdA in human-pathogenic fungi may reveal a novel antifungal target for future drug development.

scholarly journals Sterol Regulatory Element Binding Proteins in Fungi: Hypoxic Transcription Factors Linked to Pathogenesis

2010 ◽  
Vol 9 (3) ◽  
pp. 352-359 ◽  
Author(s):  
Clara M. Bien ◽  
Peter J. Espenshade
Keyword(s):  
Transcription Factors ◽  
Binding Proteins ◽  
Regulatory Element ◽  
Antifungal Drugs ◽  
Adaptation To Hypoxia ◽  
Human Pathogens ◽  
Low Oxygen ◽  
Proteolytic Activation ◽  
Content Type ◽  
Sterol Regulatory Element

ABSTRACT Sterol regulatory element binding proteins (SREBPs) are membrane-bound transcription factors whose proteolytic activation is controlled by the cellular sterol concentration. Mammalian SREBPs are activated in cholesterol-depleted cells and serve to regulate cellular lipid homeostasis. Recent work demonstrates that SREBP is functionally conserved in fungi. While the ability to respond to sterols is conserved, fungal SREBPs are hypoxic transcription factors required for adaptation to a low-oxygen environment. In the fission yeast Schizosaccharomyces pombe, oxygen regulates the SREBP homolog Sre1 by independently controlling both its proteolytic activation and its degradation. SREBP is also required for adaptation to hypoxia in the human pathogens Cryptococcus neoformans and Aspergillus fumigatus. In these organisms, SREBP is required for virulence and resistance to antifungal drugs, making the SREBP pathway a potential target for antifungal therapy.

PU.1 and p53 Double Mutant Mice Develop Aggressive AML with Dysplastic Features

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 769-769
Author(s):  
Petra Vlckova ◽  
Libor Stanek ◽  
Pavel Burda ◽  
Karin Vargova ◽  
Filipp Savvulidi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Double Mutant ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Regulatory Element ◽  
Tumour Suppressor ◽  
Mutant Mice ◽  
Stem And Progenitor Cells

Abstract Abstract 769 Introduction: Downregulation of tumour suppressor transcription factor PU.1 in haematopoietic stem and progenitor cells represents primary underlying mechanism for the development of acute myeloid leukaemia (AML) in mice with homozygous deletion of the upstream regulatory element (URE) of PU.1 gene. Human AML often display differences in aggressiveness that are associated with mutations of a well known tumour suppressor p53. We produced murine model carrying mutations of p53 and URE that develops highly aggressive AML and focused on molecular mechanisms that are responsible for AML aggressiveness. Mouse models: PU.1ure/ure (Rosenbauer F, et al. 2004) and p53−/− (Jacks T, et al. 1994) mice were used. Conditional deletion of the URE leads to downregulation of PU.1 and is marked by clonal accumulation of myeloid c-Kit+Mac-1low Gr-1low blast cells within bone marrow, spleen, and peripheral blood mirrored by lower numbers of lymphoid and erythroid cells. AML development in PU.1ure/ure mice involves a preleukaemic phase (at 2–3 months) marked by proliferation of myeloid c-Kit+Gr-1+ cells and splenomegaly. Interestingly, p53−/−mice do not develop AML, instead loss of p53 predisposes mice to solid tumours, mostly lymphomas, by 6 months of age. Results: Deletion of TP53 in the PU.1ure/ure mice (PU.1ure/ure p53−/−) results in more aggressive AML with significantly shortened overall survival, prominent hepatosplenomegaly and cachexia (wasting syndrome). Mild differences in cell surface phenotype of bone marrow derived cells were observed between PU.1ure/ure and PU.1ure/ure p53−/− mice by flow cytometry (these included: blasts expansion and lymphopenia). Next, the PU.1 expression was determined in all genotypes at progenitor and stem cell levels. PU.1 mRNA level in more aggressive PU.1ure/ure p53−/− murine AML is decreased in the entire c-Kit+tumour cell population compared to AML in PU.1ure/ure mice including haematopoietic stem and progenitor cells (HSPCs). Correspondingly to RNA level, in the PU.1ure/ure progenitors the PU.1 protein was decreased compared to p53−/− progenitors and is yet further reduced in the PU.1ure/ure p53−/− c-Kit+ Mac1+progenitors. p53−/− progenitors express similar level of PU.1 as wild type progenitors indicating that despite p53 can bind DNA as a transcription factor, it does not regulate PU.1 level directly. In addition to URE deletion we searched for other mechanisms that control PU.1 levels and found that PU.1-inhibiting microRNA miR-155 gene display altered chromatin structure and expression of both pri-miR-155 as well as its spliced mature form in the AML of PU.1ure/ure and (to higher extent in) PU.1ure/ure p53−/− murine progenitors. Upregulation of miR-155 coincides with upregulation of the Mir155hg activators: Myc and Myb. Finally, upon inhibition of either Myb or miR-155 in vitro the AML progenitors restore PU.1 levels and lose leukaemic cell growth. Conclusion: In summary, PU.1 and p53 double mutant mice develop aggressive AML with dysplastic features. Defective control of PU.1 levels in PU.1ure/ure and PU.1ure/ure p53−/−AML involves miR-155. Lastly, restored PU.1 level and cell differentiation capacity are achieved by inhibiting either Myb or miR-155 in the PU.1ure/ure p53−/− progenitors. (Grant support: P305/12/1033, UNCE 204021, PRVOUK-P24/LF1/3, SVV-2012-264507, P301/12/P380. MK was sponsored by GAUK 251070 45410, 251135 82210) Disclosures: No relevant conflicts of interest to declare.

scholarly journals Regulation of Virulence of Entamoeba histolytica by the URE3-BP Transcription Factor

mBio ◽  
2010 ◽  
Vol 1 (1) ◽  
Author(s):  
Carol A. Gilchrist ◽  
Ellyn S. Moore ◽  
Yan Zhang ◽  
Christina B. Bousquet ◽  
Joanne A. Lannigan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Entamoeba Histolytica ◽  
Liver Abscess ◽  
Intestinal Epithelium ◽  
Binding Protein ◽  
Regulatory Element ◽  
Mutant Form ◽  
Content Type ◽  
Upstream Regulatory Element

ABSTRACTIt is not understood why only some infections withEntamoeba histolyticaresult in disease. The calcium-regulated transcription factor upstream regulatory element 3-binding protein (URE3-BP) was initially identified by virtue of its role in regulating the expression of two amebic virulence genes, the Gal/GalNac lectin and ferredoxin. Here we tested whether this transcription factor has a broader role in regulating virulence. A comparison ofin vivotoin vitroparasite gene expression demonstrated that 39% ofin vivoregulated transcripts contained the URE3 motif recognized by URE3-BP, compared to 23% of all promoters (P< 0.0001). Amebae induced to express a dominant positive mutant form of URE3-BP had an increase in an elongated morphology (30% ± 6% versus 14% ± 5%;P= 0.001), a 2-fold competitive advantage at invading the intestinal epithelium (P= 0.017), and a 3-fold increase in liver abscess size (0.1 ± 0.1 g versus 0.036 ± 0.1 g;P= 0.03). These results support a role for URE3-BP in virulence regulation.IMPORTANCEAmebic dysentery and liver abscess are caused byEntamoeba histolytica. Amebae colonize the colon and cause disease by invading the intestinal epithelium. However, only one in fiveE. histolyticainfections leads to disease. The factors that govern the transition from colonization to invasion are not understood. The transcription factor upstream regulatory element 3-binding protein (URE3-BP) is a calcium-responding regulator of theE. histolyticaGal/GalNAc lectin and ferredoxin genes, both implicated in virulence. Here we discovered that inducible expression of URE3-BP changed trophozoite morphology and promoted parasite invasion in the colon and liver. These results indicate that one determinant of virulence is transcriptional regulation by URE3-BP.

scholarly journals Fluconazole and Voriconazole Resistance in Candida parapsilosis Is Conferred by Gain-of-Function Mutations inMRR1Transcription Factor Gene

2015 ◽  
Vol 59 (10) ◽  
pp. 6629-6633 ◽  
Author(s):  
Joana Branco ◽  
Ana P. Silva ◽  
Raquel M. Silva ◽  
Ana Silva-Dias ◽  
Cidália Pina-Vaz ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Candida Parapsilosis ◽  
Bloodstream Infections ◽  
Azole Resistance ◽  
Transcription Factor Gene ◽  
Gain Of Function ◽  
Content Type ◽  
Factor Gene ◽  
Resistant Strains

ABSTRACTCandida parapsilosisis the second most prevalent fungal agent causing bloodstream infections. Nevertheless, there is little information about the molecular mechanisms underlying azole resistance in this species. Mutations (G1747A, A2619C, and A3191C) in theMRR1transcription factor gene were identified in fluconazole- and voriconazole-resistant strains. Independent expression ofMRR1genes harboring these mutations showed that G1747A (G583R) and A2619C (K873N) are gain-of-function mutations responsible for azole resistance, the first described inC. parapsilosis.

scholarly journals Cyclic di-GMP Regulates TfoY inVibrio choleraeTo Control Motility by both Transcriptional and Posttranscriptional Mechanisms

2018 ◽  
Vol 200 (7) ◽  
Author(s):  
Benjamin R. Pursley ◽  
Michael M. Maiden ◽  
Meng-Lun Hsieh ◽  
Nicolas L. Fernandez ◽  
Geoffrey B. Severin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Vibrio Cholerae ◽  
Biofilm Formation ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Second Messenger ◽  
Bacterial Motility ◽  
Content Type ◽  
Intracellular Concentrations ◽  
Messenger Molecule

ABSTRACT3′,5′-Cyclic diguanylic acid (c-di-GMP) is a bacterial second messenger molecule that is a key global regulator inVibrio cholerae, but the molecular mechanisms by which this molecule regulates downstream phenotypes have not been fully characterized. One such regulatory factor that may respond to c-di-GMP is the Vc2 c-di-GMP-binding riboswitch that is hypothesized to control the expression of the downstream putative transcription factor TfoY. Although much is known about the physical and structural properties of the Vc2 riboswitch aptamer, the nature of its expression and function inV. choleraehas not been investigated. Here, we show that Vc2 functions as an off switch to inhibit TfoY production at intermediate and high concentrations of c-di-GMP. At low c-di-GMP concentrations, TfoY production is induced to stimulate dispersive motility. We also observed increased transcription oftfoYat high intracellular concentrations of c-di-GMP, but this induction is independent of the Vc2 riboswitch and occurs via transcriptional control of promoters upstream oftfoYby the previously identified c-di-GMP dependent transcription factor VpsR. Our results show that TfoY is induced by c-di-GMP at both low and high intracellular concentrations of c-di-GMP via posttranscriptional and transcriptional mechanisms, respectively. This regulation contributes to the formation of three distinct c-di-GMP signaling states inV. cholerae.IMPORTANCEThe bacterial pathogenVibrio choleraemust transition between life in aquatic environmental reservoirs and life in the gastrointestinal tract. Biofilm formation and bacterial motility, and their control by the second messenger molecule c-di-GMP, play integral roles in this adaptation. Here, we define the third major mechanism by which c-di-GMP controls bacterial motility. This pathway utilizes a noncoding RNA element known as a riboswitch that, when bound to c-di-GMP, inhibits the expression of the transcription factor TfoY. TfoY production switchesV. choleraemotility from a dense to a dispersive state. Our results suggest that the c-di-GMP signaling network ofV. choleraecan exist in at least three distinct states to regulate biofilm formation and motility.

scholarly journals Dsc Orthologs Are Required for Hypoxia Adaptation, Triazole Drug Responses, and Fungal Virulence in Aspergillus fumigatus

2012 ◽  
Vol 11 (12) ◽  
pp. 1557-1567 ◽  
Author(s):  
Sven D. Willger ◽  
E. Jean Cornish ◽  
Dawoon Chung ◽  
Brittany A. Fleming ◽  
Margaret M. Lehmann ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Regulatory Element ◽  
Invasive Pulmonary Aspergillosis ◽  
Fungal Growth ◽  
Drug Susceptibility ◽  
Antifungal Drugs ◽  
Fungal Virulence ◽  
Content Type ◽  
Hypoxia Adaptation ◽  
Element Binding Protein

ABSTRACTHypoxia is an environmental stress encountered byAspergillus fumigatusduring invasive pulmonary aspergillosis (IPA). The ability of this mold to adapt to hypoxia is important for fungal virulence and genetically regulated in part by the sterol regulatory element binding protein (SREBP) SrbA. SrbA is required for fungal growth in the murine lung and to ultimately cause lethal disease in murine models of IPA. Here we identified and partially characterized four genes (dscA,dscB,dscC, anddscD, here referred to asdscA-D) with previously unknown functions inA. fumigatusthat are orthologs of theSchizosaccharomyces pombegenesdsc1,dsc2,dsc3, anddsc4(dsc1-4), which encode a Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage.A. fumigatusnulldscA-Dmutants displayed remarkable defects in hypoxic growth and increased susceptibility to triazole antifungal drugs. Consistent with the confirmed role of these genes inS. pombe, both ΔdscAand ΔdscCresulted in reduced cleavage of the SrbA precursor protein inA. fumigatus. Inoculation of corticosteroid immunosuppressed mice with ΔdscAand ΔdscCstrains revealed that these genes are critical forA. fumigatusvirulence. Reintroduction of SrbA amino acids 1 to 425, encompassing the N terminus DNA binding domain, into the ΔdscAstrain was able to partially restore virulence, further supporting a mechanistic link between DscA and SrbA function. Thus, we have shown for the first time the importance of a previously uncharacterized group of genes inA. fumigatusthat mediate hypoxia adaptation, fungal virulence, and triazole drug susceptibility and that are likely linked to regulation of SrbA function.

scholarly journals The Phosphotransfer Protein CD1492 Represses Sporulation Initiation in Clostridium difficile

2016 ◽  
Vol 84 (12) ◽  
pp. 3434-3444 ◽  
Author(s):  
Kevin O. Childress ◽  
Adrianne N. Edwards ◽  
Kathryn L. Nawrocki ◽  
Sarah E. Anderson ◽  
Emily C. Woods ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Clostridium Difficile ◽  
Molecular Mechanisms ◽  
Toxin Production ◽  
Negative Regulator ◽  
Hamster Model ◽  
Content Type ◽  
Sporulation Initiation

The formation of spores is critical for the survival ofClostridium difficileoutside the host gastrointestinal tract. Persistence ofC. difficilespores greatly contributes to the spread ofC. difficileinfection (CDI), and the resistance of spores to antimicrobials facilitates the relapse of infection. Despite the importance of sporulation toC. difficilepathogenesis, the molecular mechanisms controlling spore formation are not well understood. The initiation of sporulation is known to be regulated through activation of the conserved transcription factor Spo0A. Multiple regulators influence Spo0A activation in other species; however, many of these factors are not conserved inC. difficileand few novel factors have been identified. Here, we investigated the function of a protein, CD1492, that is annotated as a kinase and was originally proposed to promote sporulation by directly phosphorylating Spo0A. We found that deletion ofCD1492resulted in increased sporulation, indicating that CD1492 is a negative regulator of sporulation. Accordingly, we observed increased transcription of Spo0A-dependent genes in theCD1492mutant. Deletion of CD1492 also resulted in decreased toxin productionin vitroand in decreased virulence in the hamster model of CDI. Further, theCD1492mutant demonstrated effects on gene expression that are not associated with Spo0A activation, including lowersigDandrstAtranscription, suggesting that this protein interacts with factors other than Spo0A. Altogether, the data indicate that CD1492 negatively affects sporulation and positively influences motility and virulence. These results provide further evidence thatC. difficilesporulation is regulated differently from that of other endospore-forming species.

scholarly journals Differential Requirement of the Transcription Factor Mcm1 for Activation of the Candida albicans Multidrug Efflux PumpMDR1by Its Regulators Mrr1 and Cap1

2011 ◽  
Vol 55 (5) ◽  
pp. 2061-2066 ◽  
Author(s):  
Selene Mogavero ◽  
Arianna Tavanti ◽  
Sonia Senesi ◽  
P. David Rogers ◽  
Joachim Morschhäuser
Keyword(s):  
Transcription Factor ◽  
Candida Albicans ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Efflux Pump ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Gain Of Function ◽  
Pathogenic Yeast ◽  
Content Type

ABSTRACTOverexpression of the multidrug efflux pump Mdr1 causes increased fluconazole resistance in the pathogenic yeastCandida albicans. The transcription factors Mrr1 and Cap1 mediateMDR1upregulation in response to inducing stimuli, and gain-of-function mutations in Mrr1 or Cap1, which render the transcription factors hyperactive, result in constitutiveMDR1overexpression. The essential MADS box transcription factor Mcm1 also binds to theMDR1promoter, but its role in inducible or constitutiveMDR1upregulation is unknown. Using a conditional mutant in which Mcm1 can be depleted from the cells, we investigated the importance of Mcm1 forMDR1expression. We found that Mcm1 was dispensable forMDR1upregulation by H2O2but was required for fullMDR1induction by benomyl. A C-terminally truncated, hyperactive Cap1 could upregulateMDR1expression both in the presence and in the absence of Mcm1. In contrast, a hyperactive Mrr1 containing a gain-of-function mutation depended on Mcm1 to causeMDR1overexpression. These results demonstrate a differential requirement for the coregulator Mcm1 for Cap1- and Mrr1-mediatedMDR1upregulation. When activated by oxidative stress or a gain-of-function mutation, Cap1 can induceMDR1expression independently of Mcm1, whereas Mrr1 requires either Mcm1 or an active Cap1 to cause overexpression of theMDR1efflux pump. Our findings provide more detailed insight into the molecular mechanisms of drug resistance in this important human fungal pathogen.

scholarly journals Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches

2021 ◽  
Vol 8 ◽  
Author(s):  
Eduardo Alvarado-Ortiz ◽  
Karen Griselda de la Cruz-López ◽  
Jared Becerril-Rico ◽  
Miguel Angel Sarabia-Sánchez ◽  
Elizabeth Ortiz-Sánchez ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Mevalonate Pathway ◽  
Regulatory Element ◽  
Metabolic Reprogramming ◽  
Loss Of Function ◽  
Therapeutic Approaches ◽  
Gain Of Function ◽  
The Impact

Frequent p53 mutations (mutp53) not only abolish tumor suppressor capacities but confer various gain-of-function (GOF) activities that impacts molecules and pathways now regarded as central for tumor development and progression. Although the complete impact of GOF is still far from being fully understood, the effects on proliferation, migration, metabolic reprogramming, and immune evasion, among others, certainly constitute major driving forces for human tumors harboring them. In this review we discuss major molecular mechanisms driven by mutp53 GOF. We present novel mechanistic insights on their effects over key functional molecules and processes involved in cancer. We analyze new mechanistic insights impacting processes such as immune system evasion, metabolic reprogramming, and stemness. In particular, the increased lipogenic activity through the mevalonate pathway (MVA) and the alteration of metabolic homeostasis due to interactions between mutp53 and AMP-activated protein kinase (AMPK) and Sterol regulatory element-binding protein 1 (SREBP1) that impact anabolic pathways and favor metabolic reprograming. We address, in detail, the impact of mutp53 over metabolic reprogramming and the Warburg effect observed in cancer cells as a consequence, not only of loss-of-function of p53, but rather as an effect of GOF that is crucial for the imbalance between glycolysis and oxidative phosphorylation. Additionally, transcriptional activation of new targets, resulting from interaction of mutp53 with NF-kB, HIF-1α, or SREBP1, are presented and discussed. Finally, we discuss perspectives for targeting molecules and pathways involved in chemo-resistance of tumor cells resulting from mutp53 GOF. We discuss and stress the fact that the status of p53 currently constitutes one of the most relevant criteria to understand the role of autophagy as a survival mechanism in cancer, and propose new therapeutic approaches that could promote the reduction of GOF effects exercised by mutp53 in cancer.

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