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FLASH GENE

Symbol

CDKN1C

contributors: mct/npt/pgu - updated : 27-04-2021

HGNC name	cyclin-dependent kinase inhibitor 1C (p57, Kip2)
HGNC id	1786

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	2.56 kb     4 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   silencer
text structure	silencer sequence in the promoter

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000076 3 - 1943 NP_000067 - 316 - 2020 32346031 NM_001122630 4 - 1776 NP_001116102 - 305 - 2020 32346031 NM_001122631 4 - 1771 NP_001116103 - 305 - 2020 32346031 NM_001362475 4 - 1236 NP_001349404 - 175 - 2020 32346031 NM_001362474 3 - 1935 NP_001349403 - 316 - 2020 32346031

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive mouth tooth       Homo sapiens Fetal Endocrine adrenal gland       highly Homo sapiens Fetal Reproductive female system placenta     highly   male system testis       Respiratory lung         Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Digestive odontoblast Homo sapiens Fetal

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

pregnancy

Text

placenta

IMPRINTING	paternally
text	maternally expressed, partially paternally imprinted
	maternally expressed imprinted gene with roles in embryonic development, post-natal metabolism and behaviour

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a CDK inhibitory domain
	a proline-alanine rich (PAPA), an acidic repeat region
	a conserved C terminal domain, PCNA-binding domain (pMID: 22634755)

HOMOLOGY

interspecies

homolog to murine CdKnc1c

Homologene

FAMILY

Cip/Kip cyclin-dependent kinase inhibitor family

CATEGORY

enzyme , regulatory , tumor suppressor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm
	intracellular,nucleus
text	is initially localized to the cytoplasm of activated/proliferating myoblasts, but progressive nuclear translocation leads to growth arrest during differentiation

basic FUNCTION	CDK2, CDK4 inhibitor and involved in the G1 phase arrest
	critical terminal effector of signal transduction pathways that control cell differentiation
	intrinsic inhibitor of myelinating Schwann cell differentiation, and its down-regulation is a prerequisite to allow differentiation to progress
	primarily promotes the intrinsic apoptotic pathways, favoring BAX activation and loss of mitochondrial transmembrane potential, consequent release of cytochrome-c into cytosol, caspase-9 and caspase-3 activation
	encodes an intrinsic inhibitor of myelinating glial cell differentiation
	coordinates multiple stages of corticogenesis and exhibits distinct and common activities compared with CDKN1B
	CDKN1B, CDKN1C cooperate to maintain hematopoietic stem cell quiescence through interactions with HSPA8
	CDKN1B and CDKN1C control neuronal output for distinct cortical layers by regulating different stages of precursor proliferation
	able to enhance mitochondrial-mediated apoptosis, and CDKN1C control of actin cytoskeleton dynamics is responsible for its mitochondrial pro-apoptotic effect
	in primary hepatocellular carcinoma, HES1 protein expression inversely correlates with CDKN1C/P57 mRNA levels
	intrinsic regulator of late gliogenesis and in oligodendroglial precursor cells its inhibition leads to accelerated maturation
	regulates glial fate decision in adult neural stem cells
	AHI1 and CDKN1C exhibit opposite expression patterns, where AHI1 is expressed in poor and intermediate prognosis patients, while CDKN1C is expressed in favourable prognosis patients
	functions as a negative regulator of cell proliferation through G1 phase cell cycle arrest
	cyclin-dependent kinase Inhibitor and negative regulator of cellular proliferation
	critically involved in regulating cell cycle and cellular differentiation during development
	CDKN1C expression and methylation may associate with cell cycle exit and differentiation of odontoblasts
	critical role for Cdkn1c in regulating adult adipose tissue, with modest changes in expression capable of protecting against both age and diet-induced obesity and metabolic syndrome
	CDKN1c activity is restricted to differentiating myoblasts by regulated cyto-nuclear relocalization, coordinating the balance between proliferation and growth arrest
	exhibits maternal expression, and is essential for cerebral cortex development
	regulates likely cortical development through distinct cell-autonomous and non-cell-autonomous mechanisms

CELLULAR PROCESS	cell life, differentiation

PHYSIOLOGICAL PROCESS

text	regulator of cell cycle
	controlling differentiation of skeletal muscle and alveoli in the lung in parallel with P21 and myogenin

PATHWAY

metabolism

signaling

signal transduction

a component

INTERACTION

DNA

RNA

small molecule

protein	interacts with LIMK1 (down-regulation could regulate the subcellular distribution of LIMK1 affecting the equilibrium of enzymes and regulators that control cytoskeletal dynamics)
	CDKN1C interacts with the actin cytoskeleton modifying enzyme, LIM-kinase 1 (LIMK1) but not LIMK2 (CDKN1C control of LIMK1 ultimately affects cell mobility negativel)
	E2F1-CDKN1C interaction mediated by two E2F domains (a central E2F1 domain interacts directly with CDKN1C, whereas a C-terminal E2F1 domain interacts with CDKN1C via interaction with Rb)
	drives potentially muscle differentiation through a positive feedback loop with MYOD1
	EZH2 acts as an oncogene in tumorigenesis of ovarian cancer with the possible mechanism to suppress the anti-oncogene CDKN1C
	interacts with both CDKN1C and CDKN1B and the subcellular localization of HSPA8 was critical to maintain HSC (hematopoietic stem cell) cycle kinetics
	LIMK1, the enzyme mediating CDKN1C effect on the actin cytoskeleton, was required for CDKN1C death promoting effect
	CDKN1C is a target of transcriptional repression by the NOTCH effector, HES1
	likely LHX6 and LHX8 negatively regulate CDKN1C expression in the prospective palate area to allow adequate levels of cell proliferation and thereby promote normal palate development
	epigenetic status of KCNQ1OT1 represents a critical determinant of the cell type-restricted expression of CDKN1C and, possibly, of its aberrant silencing in some pathological conditions

cell & other

REGULATION

activated by

E2F1 (E2F1 activates transcription of two members of the CDKN1 family CDKN1B and CDKN1C)

Phosphorylated by

MAPK14 (cell survival to various stresses depends on CDKN1C phosphorylation by MAPK14 that inhibits CDK activity)

Other	regulation by post-transcription
	downregulation of CDKN1C is involved in the cell cycle progression of vascular smooth muscle cells
	monoubiquitination might represent a CDKN1C modification that promotes (or inhibits) its interaction with an as yet unknown partner

ASSOCIATED DISORDERS

corresponding disease(s)

BWS , IMAS , SRS6

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation       in approximatively 5p100 of sporadic Beckwith-Wiedemann syndrome and 40 p100 of familial cases constitutional     --low   (imprinting domain involving KCNQ10T1/CDKN1C) in BWS tumoral     --low   in sporadic cases without deleted mutation of Beckwith Wiedemann and in large colorectal tumor constitutional     --low   in biparental complete hydatiform mole constitutional         (by silencing) associated or not with hypomethylation of KCNQ1OT1 in BWS tumoral         silenced by loss of methylation in esophageal cancer (associated with loss of CpG and histone H3 lysine 9 methylation at KCNQ1OT1) tumoral     --low   in urothelial carcinomas constitutional     --low   transiently down-regulated under inflammatory, demyelinating, pathophysiological conditions before the onset of multiple sclerosis remission tumoral     --low   associated with poor disease outcome in patients with cutaneous T-cell lymphoma, while upregulation of AHI1 shows a weak association with aggressive disease course tumoral     --over   in human retinoblastomas constitutional imprinting LOI     loss of imprinting of Cdkn1c protects against diet-induced obesity

Susceptibility

Variant & Polymorphism

Candidate gene
Marker	placental CDKN1C, PHLDA2 and IGF2 level monitoring may be useful for predicting and preventing the development of child small for gestational age (SGA)
Therapy target
	System Type Disorder Pubmed neurology neurodegenerative   silencing CDKN1C gene might provide a therapeutic tool to treat peripheral demyelinating diseases neurology acquired   silencing CDKN1C gene might provide a therapeutic tool to promote myelin restoration after traumatic injury

ANIMAL & CELL MODELS