Loss of p53 Causes Stochastic Aberrant X-Chromosome Inactivation and Female-Specific Neural Tube Defects

Delbridge, Alex R. D.; Kueh, Andrew J.; Ke, Francine; Zamudio, Natasha; El-Saafin, Farrah; Jansz, Natasha; Wang, Gaoyuan; Iminitoff, Megan; Beck, Tamara; Haupt, Sue; Hu, Yifang; May, Rose E.; Whitehead, Lachlan; Tai, Lin; Chiang, William; Herold, Marco J.; Haupt, Ygal; Smyth, Gordon K.; Thomas, Tim; Blewitt, Marnie E.; Strasser, Andreas; Voss, Anne K.

doi:10.1016/j.celrep.2019.03.048

Cited by 39 publications

(28 citation statements)

References 71 publications

(124 reference statements)

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“… 67 Furthermore, data from models of development, ageing, and cancer all indicate that molecular pathways (such as the enzyme phosphatidylinositol 3-kinase) and tumour suppressors (such as p53 and retinoblastoma protein) are sexually dimorphic and require sex-specific targeting. 54 , 59 , 68 …”

Section: Sex and Gender Differences In Major Chronic Diseasesmentioning

confidence: 99%

Sex and gender: modifiers of health, disease, and medicine

et al. 2020

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Clinicians can encounter sex and gender disparities in diagnostic and therapeutic responses. These disparities are noted in epidemiology, pathophysiology, clinical manifestations, disease progression, and response to treatment. This Review discusses the fundamental influences of sex and gender as modifiers of the major causes of death and morbidity. We articulate how the genetic, epigenetic, and hormonal influences of biological sex influence physiology and disease, and how the social constructs of gender affect the behaviour of the community, clinicians, and patients in the health-care system and interact with pathobiology. We aim to guide clinicians and researchers to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health.

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Section: Sex and Gender Differences In Major Chronic Diseasesmentioning

confidence: 99%

Sex and gender: modifiers of health, disease, and medicine

et al. 2020

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“…Accordingly, X-linked inherited diseases manifest predominantly in males, frequently at a young age. Notably, with our colleagues we recently identified that p53 drives Xi in females during development 57 , and its absence in females is fatal, largely associated with neural tube defects 58 . In contrast, most cancers arise from somatic mutations in the aging population, where we predicted alternative mechanisms must account for lower cancer incidence in females.…”

Section: Discussionmentioning

confidence: 95%

Identification of cancer sex-disparity in the functional integrity of p53 and its X chromosome network

Haupt

Caramia

Herschtal³

et al. 2019

Nat Commun

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The disproportionately high prevalence of male cancer is poorly understood. We tested for sex-disparity in the functional integrity of the major tumor suppressor p53 in sporadic cancers. Our bioinformatics analyses expose three novel levels of p53 impact on sex-disparity in 12 non-reproductive cancer types. First, TP53 mutation is more frequent in these cancers among US males than females, with poorest survival correlating with its mutation. Second, numerous X-linked genes are associated with p53, including vital genomic regulators. Males are at unique risk from alterations of their single copies of these genes. High expression of X-linked negative regulators of p53 in wild-type TP53 cancers corresponds with reduced survival. Third, females exhibit an exceptional incidence of non-expressed mutations among p53-associated X-linked genes. Our data indicate that poor survival in males is contributed by high frequencies of TP53 mutations and an inability to shield against deregulated X-linked genes that engage in p53 networks.

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“…This was recently shown to be caused by incomplete X-inactivation and disruptions in X-gene dosage [227]. p53 directly regulates the long non-coding RNA X-inactivation specific transcript (Xist), which is a primary effector of Xinactivation, and the loss of p53 decreases Xist expression [228].…”

Section: Sex Differences In P53mentioning

confidence: 99%

Sex differences in cancer mechanisms

et al. 2020

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We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab-and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients.

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Loss of p53 Causes Stochastic Aberrant X-Chromosome Inactivation and Female-Specific Neural Tube Defects

Abstract: Highlights d p53/Bim double knockout causes fully penetrant, femalespecific neural tube defects d p53 binds to sites in the X chromosome inactivation center d Loss of p53 results in marked reduction of Xist RNA levels d Absence of p53 causes biallelic expression of X chromosome genes

Cited by 39 publications

References 71 publications

Sex and gender: modifiers of health, disease, and medicine

Sex and gender: modifiers of health, disease, and medicine

Identification of cancer sex-disparity in the functional integrity of p53 and its X chromosome network

Sex differences in cancer mechanisms

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